International Journal of

Molecular Sciences

Review
Neurotrophic Factor BDNF, Physiological Functions
and Therapeutic Potential in Depression,
Neurodegeneration and Brain Cancer
Luca Colucci-D’Amato 1,2, * , Luisa Speranza 3 and Floriana Volpicelli 4
1 Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,
University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
2 InterUniversity Center for Research in Neurosciences (CIRN), University of Campania "Luigi Vanvitelli",
80131 Naples, Italy
3 Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA;
luisa.speranza@einsteinmed.org
4 Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II,
80131 Naples, Italy; floriana.volpicelli@unina.it
* Correspondence: luca.colucci@unicampania.it; Tel.: +39-0823-274577




Received: 29 September 2020; Accepted: 19 October 2020; Published: 21 October 2020


Abstract: Brain-derived neurotrophic factor (BDNF) is one of the most distributed and extensively
studied neurotrophins in the mammalian brain. BDNF signals through the tropomycin receptor kinase
B (TrkB) and the low affinity p75 neurotrophin receptor (p75NTR). BDNF plays an important role in
proper growth, development, and plasticity of glutamatergic and GABAergic synapses and through
modulation of neuronal differentiation, it influences serotonergic and dopaminergic neurotransmission.
BDNF acts as paracrine and autocrine factor, on both pre-synaptic and post-synaptic target sites.
It is crucial in the transformation of synaptic activity into long-term synaptic memories. BDNF
is considered an instructive mediator of functional and structural plasticity in the central nervous
system (CNS), influencing dendritic spines and, at least in the hippocampus, the adult neurogenesis.
Changes in the rate of adult neurogenesis and in spine density can influence several forms of learning
and memory and can contribute to depression-like behaviors. The possible roles of BDNF in neuronal
plasticity highlighted in this review focus on the effect of antidepressant therapies on BDNF-mediated
plasticity. Moreover, we will review data that illustrate the role of BDNF as a potent protective
factor that is able to confer protection against neurodegeneration, in particular in Alzheimer’s
disease. Finally, we will give evidence of how the involvement of BDNF in the pathogenesis of brain
glioblastoma has emerged, thus opening new avenues for the treatment of this deadly cancer.

Keywords: BDNF; miRNAs; neurogenesis; synaptic plasticity; depression; neurodegeneration;

glioblastoma

1. Introduction
The neurotrophin BDNF is one of the most studied and well characterized neurotrophic factors in
the CNS. It regulates many different cellular processes involved in the development and maintenance
of normal brain function by binding and activating the TrkB, a member of the larger family of
Trk receptors. In the brain, BDNF is expressed by glutamatergic neurons [1], glial cells, such as
astrocytes isolated from the cortex and hippocampus, but not from the striatum [2], and microglia [3].
During embryogenesis, BDNF–TrkB signaling promotes the differentiation of cortical progenitor cells
and later promotes differentiation of cortical progenitor cells into neurons (i.e., neurogenesis) [4].
Several lines of evidence also suggest that the BDNF/TrkB signaling is involved in adult neurogenesis

Int. J. Mol. Sci. 2020, 21, 7777; doi:10.3390/ijms21207777 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2020, 21, 7777 2 of 29

in the hippocampus with differing effects in the dentate gyrus (DG) and subventricular zone (SVZ) [5].
Adult neurogenesis in the dentate gyrus is enhanced by voluntary exercise, exposure to an enriched
environment, and chronic antidepressant administration. Recently, it has also been proposed that
caloric restriction and intermittent fasting in particular, appears to positively modulate hippocampal
neurogenesis and BDNF [6]. The connection between BDNF and the modulation of hippocampal
neurogenesis by external stimuli is a topic that has been extensively studied in recent years [7]. It has
been demonstrated that voluntary physical exercise, like an enriched environment, increases expression
of BDNF in the hippocampus [8], as well as hippocampal neurogenesis [9]. Physical exercise is one
particularly effective strategy for increasing circulating levels of BDNF [10,11] and improving brain
function [12–14].
In addition, studies also show that BDNF is an important regulator of synaptic transmission and
long-term potentiation (LTP) in the hippocampus and in other brain regions. The effects of BDNF on
LTP are mediated by the TrkB receptor. Especially in the hippocampus, this neurotrophin is thought to
act on both the pre- and post-synaptic compartments, modulating synaptic efficacy, either by changing
the pre-synaptic transmitter release, or by increasing post-synaptic transmitter sensitivity [15,16] to
induce a long-lasting increase in synaptic plasticity. Additionally, converging data now suggest a role
for BDNF in the pathophysiology of brain-associated illnesses. Deficits in BDNF signaling are reported
to contribute to the pathogenesis of several major diseases, such as Huntington’s disease, Alzheimer’s
disease (AD), depression, schizophrenia, bipolar, and anxiety disorders. Thus, manipulating the BDNF
signaling may present a viable approach to treat a variety of neurological and psychiatric disorders.
BDNF protein is also detectable outside of the nervous system in several non-neuronal tissues, such as
in endothelial cells [17,18], cardiomyocytes [19], vascular smooth muscle cells [17], leukocytes [20],
platelets [21,22], and megakaryocytes [19]. Therefore, it may also be involved in cancer, angiogenesis,
reduction of glucose production from the liver [23], and in the uptake of glucose in peripheral tissues
(see [24] for review). In addition, BDNF promotes the development of neuromuscular synapses and
is required for fiber-type specification, suggesting a potential role as a therapeutic target in muscle
diseases [25]. In this review, first we examine the currently known mechanisms of BDNF signaling,
information essential for the creation of BDNF-based therapeutics. Next, we focus on the effects of
antidepressants on BDNF-mediated plasticity. Additionally, we highlight the function of BDNF as a
potent factor capable of conferring protection against neurodegeneration. Finally, we touch on the
newly emerging role of BDNF in the pathogenesis of brain gliomas.

2. The Human BDNF Gene: Transcripts and Variants

2.1. BDNF Transcripts

The BDNF gene codes for a neurotrophin that is highly expressed in the CNS [26]. At the beginning
of 2000s, the only data available about the structure and regulation of the BDNF gene were from
Timmusk and colleagues, which identified in rats four 5’ exons linked to separate promoters and one 3’
exon encoding the preproBDNF protein [27–29]. These four BDNF promoters owned multiple points
of BDNF mRNA regulation and suggested an activity-dependent regulation [28–31]. Further studies,
published in 2007, clarified that BDNF has a complex gene structure with 11 different exons in humans,
nine different exons in rodents, and nine alternative promoters for both groups [32,33]. Despite this
complexity, the coding sequence is located in exon IX in both human and rodents. The latter includes
the common sequence that encodes for the proBDNF protein. All other exons are untranslated regions
with a start codon present in exons I, VII, VIII, and IX of the human BDNF gene. Exon IX is present in
all BDNF mRNA isoforms. It is supposed that the nine alternative promoters can regulate the complex
spatio-temporal expression of BDNF gene and allow BDNF to respond to a greater variety of stimuli.
For instance, in human brain tissues, all exons are expressed, but to different degrees and in different
brain structures [33]. Human heart tissue, instead, expresses high levels of BDNF isoforms containing
exon IV and exon IX [33].
Int. J. Mol. Sci. 2020, 21, 7777 3 of 29

Currently, two BDNF promoters, promoter I and promoter IV, have been well characterized
for their response after the activation of the L-type voltage gated calcium channel (L-VGCC) or
the n-methyl-d-aspartate (NMDA) receptor. Activation of L-VGCC and NMDA receptors mediate
intracellular Ca2+ -signaling and regulate several aspects of brain functions (for review [34,35]). Promoter
I is more responsive to neuronal activity and induces activity-dependent expression of BDNF in vitro
and in vivo. It contains calcium-responsive elements (CaREs) and cyclic adenosine monophosphate
(cAMP)/calcium response element (CRE) [29,36–38]. Deletion of CRE or overexpression of dominant
negative of CREB (cAMP-response element-binding protein) significantly impairs rat BDNF promoter
I response to neuronal depolarization [38]. Human BDNF promoter I is similar to rat promoter, since
an orthologous CRE-like element is also present [39]. However, mutation of this site did not affect
human BDNF promoter I response to depolarization [39]. Human BDNF promoter I also contains
an activator protein 1 (AP1) -like element and an asymmetric E-box-like element [39]. Mutation in
E-box-like element reduces human BDNF promoter I induction, impairing the response to neuronal
depolarization [39].
Another highly characterized BDNF promoter is the BDNF promoter IV that contributes
significantly to activity-dependent BDNF transcription. Human and rat BDNF promoter IV are
similar. In this promoter, three CaREs and three other regulatory elements involved in regulating
rat BDNF promoter response to NMDA receptor activation have been identified [40]. NMDA
receptor activation is capable of triggering BDNF exon IV transcription through a protein-signaling
cascade requiring extracellular signal-regulated kinase (ERK), Ca2+ /calmodulin-dependent protein
kinase (CaMK) II/IV, phosphoinositide 3-kinases (PI3K), and phospholipase C (PLC). BDNF exon IV
expression also seems capable of further stimulating its own expression through TrkB activation [41].
Additionally to the CaREs, two positive regulators have been identified: the NF-kB (nuclear factor
kappa-light-chain-enhancer of activated B cells) [42] and NFAT (nuclear factor of activated T-cells)
binding sites [30,43]. In contrast to these positive regulators, BDNF promoter IV also contains a
negative regulatory element, the class B E-box. This is a binding site for a basic helix-loop-helix protein,
BHLHB2, a suppressor of the bHLH gene superfamily [43,44]. NMDA treatment is able to remove
BHLHB2 binding to the E-box and to increase rat BDNF promoter IV activity [43,44]. Disruption of
BDNF promoter IV in mice significantly reduced the number of parvalbumin GABAergic neurons in the
prefrontal cortex and impaired GABAergic activity [45]. These mice displayed depression-like behavior
such as anhedonia-like behavior and increased latency to escape in the learned helplessness test [45].
Further evidence suggests a relationship between stress exposure and epigenetic regulation of BDNF
promoter IV with the development of psychiatric disorders. Specifically, changes in BDNF promoter
IV methylation levels are implicated in depression [46,47]. Preliminary evidence has demonstrated
that patients with major depressive disorder (MDD) present a hypomethylation of the CpG-87 site
of the promoter IV region of BDNF gene and are less likely to benefit from antidepressants [47,48].
In addition, BDNF disruption from promoter IV-derived transcripts impairs fear expression in mice,
suggesting that cells expressing BDNF from promoter IV critically regulate hippocampal-prefrontal
plasticity during fear memory [49,50].

2.2. miRNAs and BDNF

MicroRNAs (miRNAs) are a class of evolutionary conserved small non-coding single-strand RNA
molecules, 18–25 nucleotide long, able to bind to 30 untranslated regions (30 UTR) of target mRNAs
and promote their degradation or suppress their translation into proteins. MiRNAs are expressed
abundantly within the nervous system in a tissue-specific manner and are crucial players in several
biological processes, including neurogenesis, neuronal maturation, synapse formation, axon guidance,
neurite outgrowth and neuronal plasticity [51–53]. Accumulating data indicate that synthesis of BDNF
may be affected by miRNAs, indeed, a regulatory negative feedback loop between BDNF and miRNAs
exists. That is, while BDNF treatment stimulates neuronal miRNAs expression, miRNAs generally
inhibit the expression of BDNF [54]. This negative feedback loop is maintained in a state of equilibrium
Int. J. Mol. Sci. 2020, 21, 7777 4 of 29

in normal cells. Alterations in miRNAs or in BDNF contribute to the pathogenic mechanisms involved
in neurodegenerative diseases or neuropsychiatric disorders.
A number of recent studies, obtained from high throughput sequencing screening of different
brain regions or from neurological disorders, have identified seven miRNAs (miR-15a, miR-206,
miR-155-5p, miR-16, miR-103-3p, miR-330-3p, Let-7a-3p) correlated with BDNF [55]. Previous data
published by Schratt et al. reported the involvement of miR-134 in BDNF-regulated dendritic spine
size in hippocampal neurons. They demonstrate that miR-134 negatively regulates the spine size
via repressing the translation of LIM kinase 1, which is known to regulate dendritic structures.
BDNF is able to relieve the inhibition of LIM kinase 1 translation, and in this manner contribute
to synaptic development, maturation and/or plasticity [56]. Recently, Baby et al. [57] found that
miR-134 mediates post-transcriptional regulation of CREB1 and BDNF, as previously described by
Gao et al. [58], who demonstrated that mutant mice lacking Sirtuin 1 (SIRT1) catalytic activity shows
reduction in both CREB and BDNF proteins and upregulation of miR-134. Thus, higher levels of
miR-134 negatively regulate synaptic plasticity [58]. MiR-134-mediated post-transcriptional regulation
of CREB1 and BDNF prevents cognitive deficits in chronic unpredicted mild stress model (CUMS) [59].
At the same time, data published by Xin and coworkers [60] demonstrate that miR-202-3p silencing
reduces the damage to hippocampal nerve in CUMS rats through the upregulation of BNDF expression.
miRNAs could be an effective target also for the treatment of depression. Recent data demonstrate that
miR-124-mediated post-transcriptional regulation of CREB1 and BDNF can improve depression-like
behavior in a rat model [61]. Instead, miR-153 through the inhibition of activation of the JAK-STAT
signaling pathway improves BDNF expression and influences the proliferative ability of hippocampal
neurons in autistic mice [62].
In vitro studies have also allowed analysis of the effect of neurotoxins or anesthetic agents
on miRNAs expression and in turn, on BDNF expression. For instance, differentiated PC12 cells,
treated with 1-methyl-4-phenylpyridinium (MPP), show upregulation of miR-34a, miR-141, and miR-9,
suggesting that perturbed expression of them may contribute to Parkinson’s disease (PD)-related
pathogenic processes, probably by affecting the expression of B-cell lymphoma 2 (BCL2), BDNF,
and SIRT1 as potential targets [63].
Instead, studies in vitro on embryonic stem cell-derived neurons demonstrated that inhibition of
miR-375 and miR-107 ameliorates ketamine-induced neurotoxicity via inverse regulation of the BDNF
gene [64,65].
In summary, understanding the different functions of the various BDNF transcripts, the modulation
of the expression of specific exons, and investigating the function of the BDNF-related miRNAs may
represent a promising strategy to restore enduring changes in gene expression in response, for example,
to environmental insults. This, in turn, might open new therapeutic perspectives for the treatment of
neurodegenerative and neuropsychiatric disorders.

2.3. Biology of BDNF

Synthesis and maturation of BDNF is a multistage process, involving the formation of several
precursor isoforms. The BDNF protein, discovered in 1982 [66], is a highly conserved protein of
247 amino acids, synthesized and folded in the endoplasmic reticulum as preproBDNF (32–35 kDa).
Upon translocation to the Golgi apparatus, the signal sequence of the preregion is rapidly cleaved,
and the isoform proBDNF (28–32 kDa) is generated [67]. The proBDNF is further cleaved to reach
the mature isoform (mBDNF, 13 kDa) [67,68]. Intracellular proteolytic cleavage of proBDNF may
occur by the subtilisin-kexin family of endoproteases such as furin, or in intracellular vesicles by
convertases [69,70] (Figure 1).
Int. J. Mol. Sci. 2020, 21, 7777 5 of 29
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Figure 1. Brain-derived neurotrophic factor (BDNF) protein structure. The preproBDNF consists of
Figure 1. Brain-derived
three sequences: neurotrophic
signal sequence (s.s),factor (BDNF) and
pro-domain, protein structure.
mature domain. TheThe
preproBDNF consists of
intra- or extracellular
three sequences:
cleavage signal sequence
of preproBDNF generates(s.s), pro-domain,
functionally activeand matureBDNF
isoforms: domain. The intra-
pro-peptide andormature
extracellular
BDNF
cleavage
(mBDNF),ofeachpreproBDNF generates
of which exhibits functionally affinity
a characteristic active isoforms: BDNF
to a specific type pro-peptide and mature
of receptor. Arrowheads
BDNF
indicate(mBDNF), each of
known protease whichsites
cleavage exhibits a characteristic
involved affinity
in the processing to a specific
of mature typeposition
BDNF. The of receptor.
of the
Arrowheads indicate known protease cleavage sites involved in the processing of mature
single nucleotide polymorphism (rs6265, Val66Met) and the substitution of valine (Val) in methionine BDNF. The
position of the single
(Met) at codon (aa) 66nucleotide polymorphism
in the human BDNF gene(rs6265, Val66Met)
is indicated by an and the substitution of valine (Val)
arrow.
in methionine (Met) at codon (aa) 66 in the human BDNF gene is indicated by an arrow.
Extracellular cleavage of proBDNF is determined by plasmin [71] and matrix metalloproteases
2 andExtracellular
9 (MMP2 andcleavageMMP9) of proBDNF
[72,73]. is determined
Depending on the cellbytype,
plasmin
BDNF [71] and
can be matrix
secretedmetalloproteases
in a constitutive
2or and 9 (MMP2 andmanner
activity-dependent MMP9) [72,73].
[74]. Depending
In neuronal on the
cells, both cell type,
proBDNF BDNF can
and mBDNF be secreted
are released in a
following
constitutive
cell membrane or depolarization
activity-dependent [75–77].manner [74]. Inofneuronal
The balance proBDNFcells, both proBDNF
and mBDNF dependsand mBDNF
on the are
particular
released following
stages of brain cell membrane
development depolarization
and regions. In the early[75–77].
postnatalTheperiod,
balance theof proBDNF and
concentration mBDNF
of proBDNF
depends
is higher on
and the particular
may stages ofasbrain
be considered development
an important and
factor regions. Inbrain
modulating the early postnatal
function; period,
while mBDNF the
concentration of proBDNF
prevails in adulthood and isisimportant
higher and may
for be considered
processes occurring as in
anadulthood,
important factor
such as modulating
neuroprotectionbrain
function; while
and synaptic mBDNF[78].
plasticity prevails
Bothin adulthood
proBDNF andand is important
mBDNF for processes
are active, eliciting occurring in adulthood,
opposing effects via the
such as neuroprotection
p75 neurotrophin receptorand(p75NTR),
synaptic plasticity
a member[78]. Both
of the proBDNF
tumor necrosis andfactor
mBDNF (TNF) are receptor
active, eliciting
family
opposing effects via
and TrkB receptor, the p75 neurotrophin
respectively. receptor
In resting form, both(p75NTR), a member
types of receptor areof the tumor
located in thenecrosis
membrane factor
of
(TNF) receptor
intracellular familyStimulation
vesicles. and TrkB receptor,
with cAMP, 2+
respectively. In resting
Ca , or electrical form, both
impulse types
initiates of transfer
their receptor andare
located in the
fusion with themembrane of intracellular
cellular membrane [79,80].vesicles. Stimulation with cAMP, Ca2+, or electrical impulse
initiates
Thetheir transfer
mature domain and fusion
of proBDNFwith the cellular preferentially
interacts membrane [79,80]. with p75NTR, mediating synaptic
The in
pruning mature domainbrain
the prenatal of proBDNF interactsthrough
[81]. ProBDNF, preferentially with p75NTR,
its pro-domain, can also mediating synaptic
interact with the
pruning in the prenatal
sortilin receptor or otherbrain
vacuolar [81].protein
ProBDNF, through
sorting its pro-domain,
10 protein (Vps10p) (Figure can also 2). interact with the
Thus, proBDNF
sortilin
bindingreceptor
to specificor receptors
other vacuolartriggersprotein sorting
signaling 10 protein
pathways, (Vps10p)
which (Figure 2).neuronal
can determine Thus, proBDNF
fate via
binding
promoting to their
specific
deathreceptors triggers
or survival signaling
[82,83]. pathways, which can determine
The proBDNF/p75NTR/sortilin binding neuronal fate via
complex initiates
promoting their death
signaling cascades or survival
leading [82,83]. The
to the activation of proBDNF/p75NTR/sortilin
c-Jun amino terminal kinase binding
(JNK).complex initiates
This pathway is
signaling
involved in cascades
neuronal leading to the
apoptosis activation
[82,83]. Highof c-Junofamino
levels p75NTR terminal kinase
expression are(JNK).
detectedThisduring
pathway is
brain
involved
developmentin neuronal apoptosis [82,83].
and post-traumatic High[84].
recovery levels
Whenof p75NTR
matureexpression
domain ofare BDNF detected
bindsduring brain
to p75NTR,
development and post-traumatic recovery
the RIP2 (serine/threonine-protein [84]. When
kinase 2)/TRAF6 mature
(tumor domainfactor
necrosis of BDNF bindsassociated
receptor to p75NTR, the
factor
RIP2 (serine/threonine-protein
6)-mediated pathway is initiated, kinase
which2)/TRAF6
leads to(tumor
NF-kBnecrosis
activation factor receptor
[82,85]. The associated
activation of factor
NF-kB6)-
mediated pathway survival
promotes neuronal is initiated,
andwhich leads toduring
maintenance NF-kBbrainactivation
development[82,85].[85].
The In activation
addition,ofp75NTR
NF-kB
promotes neuronal
interacts also with the survival and maintenance
Ras homologous (Rho) during
proteinbrain
family.development
This pathway [85].isIn addition,
reported to p75NTR
regulate
interacts
neuronal also
growthwith the development
cone Ras homologous (Rho) protein
and motility [85]. family. This pathway is reported to regulate
neuronal growth cone development and motility [85].
Int. J. Mol. Sci. 2020, 21, 7777 6 of 29
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Figure
Figure2.2.Intracellular
Intracellularsignaling
signalingcascades
cascadesactivated
activatedby byinteraction
interactionofofBDNF
BDNFisoforms
isoformswith withits
itsreceptors.
receptors.
proBDNF
proBDNF and mBDNF bind to different receptors, respectively. The mBDNF isoform highest
and mBDNF bind to different receptors, respectively. The mBDNF isoform exhibits exhibits
affinity
highest for the for
affinity tyrosine kinasekinase
the tyrosine B receptor (TrkB)
B receptor receptor,
(TrkB) receptor,which
which when
whenstimulated
stimulatedundergoes
undergoes
homodimerization
homodimerizationand andautophosphorylation,
autophosphorylation,but butalso
alsobinds
bindsthethelow
lowaffinity
affinityneurotrophin
neurotrophinreceptor
receptor
p75NTR. The interaction between the TrkB receptor and the p75NTR receptor
p75NTR. The interaction between the TrkB receptor and the p75NTR receptor in a complex increases in a complex increases
the
theligand
ligandbinding
bindingaffinity
affinityto toBDNF.
BDNF. Sortilin
Sortilin isis considered
considered aa co-receptor
co-receptor forfor p75NTR.
p75NTR.The TheproBDNF
proBDNF
isoform, consisting of two sequences (pro-domain and mature
isoform, consisting of two sequences (pro-domain and mature domain), interacts with specificdomain), interacts withreceptors,
specific
receptors,
sortilin and sortilin
p75NTR,and p75NTR,
respectively.respectively.
The binding The ofbinding
proBDNF of proBDNF to a p75NTR/sortilin-complex
to a p75NTR/sortilin-complex induces
induces
signaling signaling
pathways pathways
that arethat are specific
specific for proBDNF.
for proBDNF. The binding
The binding of proBDNF
of proBDNF in combination
in combination with
with sortilin causes the involvement of neurotrophin receptor-interacting
sortilin causes the involvement of neurotrophin receptor-interacting factor (NRIF), tumor necrosis factor (NRIF), tumor
necrosis factor receptor-associated
factor receptor-associated factor 6 (TRAF6),
factor 6 (TRAF6), and neurotrophin
and neurotrophin receptor-interacting
receptor-interacting MAGE homologue MAGE
homologue (NRAGE)
(NRAGE) proteins. Thisproteins.
pathwayThis pathway
activates activates the JNK-associated
the JNK-associated pathwayprogrammed
pathway that promotes that promotes cell
programmed cell death, or the receptor-interacting
death, or the receptor-interacting serine/threonine-protein kinase 2 (RIP2) /TRAF6-mediated
serine/threonine-protein kinase 2 (RIP2) /TRAF6-
pathway
mediated
is initiated.pathway is initiated.
Multi-subunit Multi-subunit
IκB kinase IκB kinase (IKK)
(IKK) phosphorylates phosphorylates
(orange (orangeofdot)
dot) the inhibitor the
kB (IkB)
inhibitor of kB (IkB) protein, which results in dissociation of IkB from NF-κB.
protein, which results in dissociation of IkB from NF-κB. The activated nuclear factor kappa B (NF-kB) The activated nuclear
factor
is then kappa B (NF-kB)
translocated is then
into translocated
the nucleus whereinto the nucleus
it binds where
to specific it binds to
sequences ofspecific
DNA and sequences
promotes of
DNA and survival
neuronal promotesand neuronal survivalIn
maintenance. and maintenance.
addition, p75NTR In interacts
addition, with
p75NTR interacts
the Rho family with the Rho
of proteins,
family
whose of proteins,mediates
activation whose activation
the activity mediates the activityprotein
of Rho-associated of Rho-associated
kinase (ROCK), protein kinase
which (ROCK),
subsequently
which
leads tosubsequently
activation ofleads the AKTto activation
pathway, of the AKT
involved inpathway,
cytoskeletalinvolved in cytoskeletal
remodeling. remodeling.
The mBDNF/TrkB The
receptor
mBDNF/TrkB
complex triggers receptor
signalingcomplex
pathwaystriggers
associated signaling pathways
with activation associated with 3-kinase
of phosphatidylinositol activation of
(PI3K),
phosphatidylinositol
phospholipase C gamma 3-kinase
(PLC-γ),(PI3K),
and phospholipase
GTP-ases of theCRho gamma
family,(PLC-γ),
involvedand GTP-asesplasticity
in survival, of the Rho and
family,
neuriteinvolved
outgrowth, in survival,
transcription plasticity and neurite
regulation, outgrowth,
and synaptic transcription regulation, and synaptic
plasticity.
plasticity.
mBDNF binds with the high-affinity TrkB receptor, the receptor dimerizes, and the intracellular
tyrosine
mBDNFresidues
bindsare
withautophosphorylated [86].
the high-affinity TrkB Phosphorylated-TrkB
receptor, activates
the receptor dimerizes, andseveral enzymes:
the intracellular
PI3K, mitogen-activated protein kinase (MAPK), PLC-γ, and guanosine triphosphate hydrolases
tyrosine residues are autophosphorylated [86]. Phosphorylated-TrkB activates several enzymes:
(GTP-ases)
PI3K, of the Rho gene
mitogen-activated family kinase
protein [87–89].(MAPK),
mBDNF-TrkB-signaling pathwaystriphosphate
PLC-γ, and guanosine regulate multiple events,
hydrolases
(GTP-ases) of the Rho gene family [87–89]. mBDNF-TrkB-signaling pathways regulate multiple
events, such as apoptosis and survival of neurons [90–92], dendritic growth [93–96], spine maturation
Int. J. Mol. Sci. 2020, 21, 7777 7 of 29

such as apoptosis and survival of neurons [90–92], dendritic growth [93–96], spine maturation and
stabilization, development of synapses [96–98], learning- and memory-processes-dependent synaptic
plasticity [99,100].
PI3K/Akt-related pathway exerts antiapoptotic and pro-survival activity and modulates NMDA
receptor-dependent synaptic plasticity [101–103]. The PI3K/Akt/mTOR cascade enhances dendritic
growth and branching through regulation of protein synthesis and cytoskeleton development [104,105].
The MAPK/Ras-signaling cascade regulates protein synthesis during neuronal differentiation [85]
and is also required for the activation of ERK 1/2 and CREB [106,107]. This pathway is crucial not only
for early response gene expression (e.g., c-Fos), but also for cytoskeleton protein synthesis (e.g., Arc
and cypin) [87], as well as dendritic growth and branching in hippocampal neurons [94,108].
The PLC-γ-dependent pathway evokes activation of CAM kinase and protein kinase C (PKC),
which subsequently increases the 1,2-diacylglycerol (DAG) and Ca2+ ion concentrations [89].
The PKC-dependent pathway is reported to enhance synaptic plasticity [85] (Figure 2).
In summary, the specific role of BDNF in the regulation of numerous brain physiological processes
depends on the interaction of its isoforms with different types of receptors. This, in turn, elicits the
activation of signaling pathways that are critical for processes of brain development, synaptic plasticity,
and protection and/or regeneration after damage. Perturbation of the BDNF synthesis, resulting in
dysfunctions of its signaling cascades, may be responsible for triggering several pathological processes.

2.4. The Human BDNF Variant Val66Met

BDNF level in the peripheral tissues, brain, and blood may be also affected by gene polymorphism.
The pro-domain of BDNF is the locus of a functional human BDNF polymorphism (SNPs) Val66Met,
also known as rs6265 or G196Apolymorphism [109]. This point mutation causes a substitution of
Valine (Val) to Methionine (Met) at codon 66 (Val66Met) in the pro-domain of BDNF (Figure 1).
The Val66Met polymorphism does not exist in the mouse or other model organisms. Thus, multiple
studies aim to mimic the function of BDNF Val66Met in cellular models or in genetically engineered
mouse models. The BDNF Val66Met variant was first identified in the late 1990s and in 2002 the
first two genetic studies investigating the BDNF Val66Met polymorphism in the pathogenesis of
neurodegenerative disease were published [110,111]. The functionality of BDNF Val66Met variant
was only confirmed in 2003 [112], where BDNF Val66Met polymorphism was shown to disrupt the
episodic memory in humans. In addition, Egan et al. [112] also demonstrated that in hippocampal
cultures BDNF Val66Met polymorphism did not alter BDNF expression per se, but the perisomatic
localization of BDNF. Then, in 2005 it was discovered that the BDNF Val66Met substitution also
disrupts the sortilin-binding site, impairing activity-mediated secretion of BDNF [113]. Likewise,
the BDNF Val66Met substitution also disrupts the translin-binding site, which impairs dendritic
targeting of BDNF mRNA [114]. Thus, the principle molecular mechanism associated with the BDNF
Val66Met polymorphism is the deficient activity-dependent release of BDNF, which consequently
impacts the efficiency of BDNF-TrkB signaling [113]. Following the demonstration that this SNP
was functionally relevant over the past 18 years, more than 1700 studies have investigated the
effects of this polymorphism on brain function in health, as well as in diseases, particularly in
neuropsychiatric disorders [115,116]. The BDNF Val66Met polymorphism has been associated with
cerebral cortex plasticity [117,118], with gray matter structures [119,120], or white matter integrities
and structural networks [121,122]. More specifically, BDNF Val66Met polymorphism is associated with
cognitive processes [112,123–127], and cognitive impairment in neurodegenerative disease, such as
Parkinson’s disease (PD) [128,129] and AD [130,131], and even more with several brain disorders,
including MDD and bipolar disorder [132–137], epilepsy [138–140], schizophrenia [125,141–144],
aging and dementia [145] and stroke [117,146,147]. Met66, but not Val66, BDNF pro-domain can
induce the growth cone retraction in young hippocampal neurons [148]. Although many studies have
demonstrated the possible genetic effects of this BDNF polymorphism in diseases or brain function,
Int. J. Mol. Sci. 2020, 21, 7777 8 of 29

other articles have failed to replicate the findings. The discrepancies of BDNF Val66Met genetic studies
may result from many factors such as environmental factors, ethnicity, age, and sex.

3. Neuroplasticity in MDD: The Effects of Antidepressant Therapies

3.1. Major Depressive Disorder

Major depressive disorder is one of the most prevalent and debilitating psychiatric disorders
with high impact on the quality of life and negative effects on mood, behavior, and cognition [149].
Over the past few decades, several mechanisms have been investigated in the pathophysiology of MDD,
including altered serotonergic, noradrenergic, dopaminergic, and glutamatergic systems, increased
inflammation, hypothalamic-pituitary-adrenal axis abnormalities, vascular changes, and decreased
neurogenesis and neuroplasticity. In particular, a decrease in serotonergic neurotransmission is
regarded as the main etiopathogenetic mechanism occurring in depressed patients. Thus, the most
common drugs used to treat MDD are serotonin reuptake inhibitor (SSRI) that block SERT and thus
increase serotonin in the raphe nucleus at post-synapse. Therefore, a misbalance in the serotonin
production and/or release is believed to play a central role in determining MDD. This led to finding,
by means of genetic, proteomic and pharmacological tools, molecules able to increase the expression
of serotonin in neurons by modulating neural genes or proteins [150–152]. Among these molecules,
TPH2, the rate-limiting enzyme responsible for brain serotonin biosynthesis, plays a crucial role and is
amenable of genetic and pharmacological manipulation [153,154]. Nevertheless, in 1997 Duman and
Nestler formulated the neurotrophin hypothesis of depression [155]. This theory is now supported by
studies demonstrating a decrease in BDNF mRNA and protein levels in postmortem critical regions,
such as the hippocampus, prefrontal cortex and amygdala, in patients with MDD compared to controls.

3.2. BDNF and Neuronal Plasticity

Brain development occurs through coordinated processes of neuro- and gliogenesis, formation of
neuronal projections and synaptogenesis, and programmed cell death and elimination of improperly
formed connections, together resulting in the formation of the functionally and morphologically
adjusted structure of the adult brain [156,157]. Neuroplasticity or brain plasticity is the ability of the
nervous system to reorganize its structure, function, and connections in response to extrinsic or intrinsic
stimuli [158]. Neuronal plasticity in rodents has been well-documented during the last decades,
whereas neuroplasticity in the human brain largely remains indirect, mostly because of methodological
limitations as well as ethical constraints. Neuronal plasticity includes different mechanisms excellently
reviewed by Castren [159]. One of these is the neurogenesis, i.e., the formation of newborn neurons in
proliferative areas. There is solid evidence that neurogenesis occurs in the adult mammalian brain.
In rodent adult brains, neurogenesis is mainly restricted to the subventricular zone and the subgranular
zone of the dentate gyrus in the hippocampus and olfactory bulbs [156]. An accumulating body of
evidence indicates that BDNF is involved in the regulation of migration of neuronal progenitors along
the rostral migratory stream and neuronal settlement in the olfactory bulb [160] and also acts during
the later stages of neurogenesis [161,162].
Neuronal plasticity is extensively studied during critical periods, a time window during the early
phase of brain development, when neuronal circuits are noticeably sensitive to being shaped by external
stimuli and experience, producing permanent and large-scale changes to neural circuits. The same
circuits can be shaped by experience later in life, but to a lesser degree. After the ending of critical
periods, neuronal plasticity and changes in network structure are more restricted. However, recent data
indicate that several drugs used for the treatment of neuropsychiatric disorders can directly induce
plasticity and reactivate a critical period-like plasticity in the adult brain. The first functional evidence
for the role of neurotrophins in plasticity was obtained in the visual cortex. The observation that BDNF
synthesis in the visual cortex is regulated by visual stimulation made BDNF the prime candidate for
this activity-dependent regulated factor [163–165]. In transgenic mice with early overexpression of
Int. J. Mol. Sci. 2020, 21, 7777 9 of 29

BDNF, an accelerated onset and end of the critical period and precocious maturation of inhibitory
circuits was observed. Conversely, mice raised in the dark and resulting in lower levels of BDNF
showed a delayed visual plasticity [166,167]. In addition, a disruption in the binding between promoter
regions of BDNF exon IV and cAMP response element-binding protein (CREB) results in decreased
inhibitory input [168], which impairs the critical period plasticity.

3.3. BDNF and Synaptic Plasticity

Another mechanism involved in neuronal plasticity is the modification of mature neuronal
morphology, involving axonal and dendritic arborization and pruning, an increase in spine density,
and synaptogenesis [169]. Epigenetic mechanisms involved in the transcriptional regulation of genes
also can contribute to synaptic plasticity. Several in vitro and in vivo studies analyzed the effects of
BDNF on plasticity. Cazorla et al. proved that 48 h of BDNF stimulation in PC12 cells, transfected
with TrkB, increased neurite outgrowth compared to the non-treated cells [170]. Interestingly, BDNF
stimulation was able to promote dendritic outgrowth and spine formation [171,172] in primary
hippocampal cells grown in B27-deprived medium. This neuroplastic effect is probably achieved
through the activation of intracellular-signaling cascades [173,174]. Recent data suggest that intracellular
overexpression of BDNF in hippocampal developing neurons induces maturation of excitatory and
inhibitory synapses, with respect to exogenous application of BDNF [175]. BDNF mice lacking BDNF die
during the second postnatal week [176] and BDNF deficit causes inhibition of dendritic arborization [92,
177] and reduction of expression of genes functionally related to vesicular trafficking and synaptic
communication [178]. Instead, heterozygous BDNF mice survive into adulthood and BDNF is
required for several forms of LTP, the main mechanism mediating plasticity [179]. At morphological
level, these mice display a specific hippocampal volume reduction [180] similar to that observed in
heterozygous TrkB mice [181,182], but in contrast to p75NTR-deficient mice [183]. These findings
suggest a link between hippocampal volume and BDNF-mediated TrkB signaling [181,182]. Over the
last years, BDNF has been extensively studied as an important regulator of synaptic transmission
and LTP in the hippocampus and in other brain regions. The effects of BDNF in LTP are mediated
by TrkB receptors. In particular, in the hippocampus the neurotrophin is thought to act at pre- and
post-synaptic levels, modulating synaptic efficacy either by changes in pre-synaptic transmitter release,
or by increased post-synaptic transmitter sensitivity (see e.g., [15,16]) to induce a long-lasting increase
in synaptic plasticity. This depends on individual circumstances. Thus, BDNF can be: (i) either,
a mediator or a modulator of synaptic plasticity, (ii) both, a neurotransmitter that acts both at pre- and
post-synaptic level simultaneously at the same individual synapse. Recent data published from Lin et al.
revealed that in CA3 or CA1 regions anterograde BDNF-TrkB signaling is involved in LTP induction,
while anterograde and retrograde BDNF-TrkB signaling contributes to LTP maintenance. BDNF in
both pre-synaptic and post-synaptic terminals modulate basal neurotransmission and pre-synaptic
TrkB, probably regulating pre-synaptic release [184]. In addition, it has also been shown that BDNF
regulates the transport of mRNAs along dendrites and their translation at the synapse. These processes
occur by modulating the initiation and elongation phases of protein synthesis, and by acting on specific
miRNAs [100]. Local protein synthesis responds with rapid and subtle modulation of the proteome to
remodel the synaptic regions in response to stimuli [185]. Protein turnover is required for synaptic
plasticity, and BDNF-signaling has been also described as a crucial regulator for maintaining the
baseline autophagic activity in the brain. BDNF deficiency causes an uncontrolled rise in autophagic
degradation [186].
BDNF is one of the most studied synaptic molecules that efficiently modify synaptic strength and
can act as a mediator, modulator, or instructor of synaptic plasticity. Specific changes in dendritic
spines, as well as in adult hippocampal neurogenesis, can be correlated to several forms of learning
and memory. BDNF is one of the most inspiring molecules to better understand the disadvantageous
synaptic learning underlying the etiology of depression, accompanied by declines in the rate of adult
neurogenesis and in spine densities [181].
Int. J. Mol. Sci. 2020, 21, 7777 10 of 29

3.4. BDNF in Depressed Patients

BDNF protein and TrkB receptor are detectable in several non-neuronal tissues, including
endothelial cells [17,18], cardiomyocytes [19], vascular smooth muscle cells [17], leukocytes [20],
megakaryocytes [19], and platelets [21,22]. Serum BDNF has been clearly demonstrated to originate
from the progenitors of platelets [21]. Platelets are the major source of peripheral BDNF and are
important for storing the BDNF secreted from other tissues [187]. Over the last years, there has been
a great interest in peripheral BDNF measures in relation to psychiatric illness. It has been studied
as biomarker reflecting these disorders [188,189]. However, there is no evidence that serum BDNF
is related to brain BDNF and neuroplasticity. Nevertheless, the low serum concentration of BDNF
has often been associated with the pathophysiology of MDD [190–192]. An aspect to consider is if the
serum BDNF levels are dependent on the release of BDNF from platelets [193]. The significance of
the lower BDNF levels in depression is currently unclear. The temporal correlation between serum
BDNF levels and the antidepressant effect seems to be indirect: ketamine and electroconvulsive
shock treatment increase serum BDNF levels only gradually, while their antidepressant effect appears
quickly [194]. There are two studies that directly observed a reduction of BDNF levels in platelets of
patients with MDD [195,196]. Another study showed that BDNF levels of platelet were significantly
decreased compared to the controls. In this study, the BDNF levels were normalized compared to
control with SSRIs treatment [197]. Taken together, these studies strongly suggest that changes in
serum BDNF levels reflect altered BDNF release from blood platelets. Thus, given the similarities
in the regulation of BDNF synthesis between megakaryocytes and neurons, there may be parallels
between the brain, BDNF in serum, and release. Nevertheless, within the CNS a reduction in BDNF
and TrkB expression has been reported in the hippocampus and prefrontal cortex of post-mortem brain
tissues of suicide victims [198,199]. In addition, several meta-analyses data confirm the association of
the Val66Met polymorphism with an increase of susceptibility to develop mood disorders [200–202].
Finally, a recent paper showed that subjects with the Met allele of the BDNF gene are more likely to
develop depression [134].
A disruption in serotonin signaling in the brain is also believed to be involved in the
pathophysiology of depression. Changes in synaptic serotonin levels and receptor levels are
coupled with altered synaptic plasticity and neurogenesis [203,204]. It has been proposed that
chronic treatment with conventional antidepressants, such as SSRIs, but not acute administration
increases neurogenesis [205–207] and selective SSRIs might reactivate serotonin’s ability to mediate
developmental plasticity. BDNF acts as a modulator of the 5-HT system and vice versa, acting as the
link between the antidepressant drug and the neuroplastic changes. Close molecular connections
between serotonin receptors and neurotrophic proteins such as BDNF and intracellular signaling
cascades are responsible for cytoskeletal rearrangement [169,208–211]. Thus, dysregulation in
5-HT–BDNF interaction may be responsible for the development of neuropsychiatric and behavioral
abnormalities [212].
Understanding the function of the members of the BDNF system in response to the challenges of
the environment and the interaction with different 5-HT receptors in health and disease will lead to
new classes of drugs that could be used in therapy for psychiatric and neurodegenerative disorders.

3.5. Effect of Antidepressant Therapies on Plasticity BDNF-Mediated

3.5.1. BDNF and Antidepressant Treatments

Multiple lines of evidence suggest that antidepressant treatments increase BDNF mRNA and
protein levels in the cerebral cortex and hippocampus (for review see [213,214]). This increase is
partly due to a reduction of histone acetylation in the BDNF promoter regions. The involvement of
BDNF in the efficacy of antidepressant treatments has mainly been demonstrated in rodent models.
It has been demonstrated that all pharmacological classes of clinical antidepressants increase TrkB
autophosphorylation and signaling in the hippocampus and forebrain, effects observed within hours
Int. J. Mol. Sci. 2020, 21, 7777 11 of 29

after the administration of the drug [203,215]. Similar results in BDNF mRNA and TrkB phosphorylation
have been observed after acute treatment with ketamine [216–219]. In rodents, injection of BDNF
in the hippocampus reduces depression-like behavior [220], in contrast injection of BDNF into the
nucleus accumbens or ventral tegmental area promotes depressive effects [221], demonstrating the
network-dependent effect of BDNF in mood regulation. Interestingly, conditional knockout of BDNF
in forebrain regions increases depressive behavior in females, but not in male mice [222], and blocks
the effects of antidepressants desipramine or ketamine [216,223]. Similarly, conditional deletion of
TrkB in dentate gyrus or inhibition of TrkB signaling by a dominant-negative TrkB receptor blocks the
effects of antidepressants [224,225]. In addition, mice with Val66Met polymorphism are insensitive
to antidepressants [226]. Recent evidence demonstrates that the antidepressant effects of GLYX-13,
a novel glutamatergic compound that acts as an NMDA modulator with glycine-like partial agonist
properties, are blocked by intra-medial prefrontal cortex infusion of an anti-BDNF antibody or in mice
with a knock-in of the BDNF Val66Met allele. Pharmacological inhibition of BDNF-TrkB signaling
or L-type voltage-dependent Ca2+ channels (VDCCs) blocks the antidepressant behavioral actions of
GLYX-13 [227].
Taken together, these data suggest that BDNF serves as a transducer, acting as the link
between the antidepressant drug and the neuroplastic changes that result in the improvement
of depressive symptoms.

3.5.2. Beneficial Effects of Exercise on Plasticity: The Role of BDNF

Several lines of evidence suggest that exercise has beneficial effects on plasticity and BDNF could
be a link between plasticity and physical activity. Although it has been proven that exercise in MDD
patients reduced depressive symptoms [228–230], neuroplasticity per se has not yet been monitored
in these patients. However, voluntary physical exercise, like an enriched environment, increases
expression of BDNF in the hippocampus [8], as well as hippocampal neurogenesis [9] and this could
improve brain function by enhancing plasticity, cognition, learning, and memory [12–14]. Physical
exercise is one particularly effective strategy for increasing circulating levels of BDNF [10,11]. It has
repeatedly been demonstrated that an acute bout of aerobic exercise transiently increases both serum
and plasma BDNF in an intensity-dependent manner [10,11]. Exercise increases the release of BDNF
from the human brain [231,232] suggesting that exercise also mediates central BDNF production in
humans. It has been suggested that miR-34a potentially can also mediate changes in BDNF expression
and may reflect the decrease in performance after overtraining [233].
Multiple studies suggest that BDNF has a dominant role in mediating the effects of physical
activity on cognitive changes [234]. It has been shown that three months of aerobic exercise training
increases hippocampal volume in healthy individuals and in patients with schizophrenia by 12% and
16%, respectively [235]. The question whether exercise regulates muscle-derived circulating factors that
can pass through the blood–brain barrier and stimulate BDNF production in the brain remains unclear.
In 2016, Moon et al. show that the myokine cathepsin B (Ctsb) might be involved in mediating the
exercise-induced improvement in hippocampal neurogenesis, memory, and learning [236]. Mice lacking
Ctsb showed depression-like symptoms when they were forced to swim [236].
Other papers have demonstrated that exercise induces upregulation in skeletal muscle of PGC1α,
a transcriptional co-activator of mitochondrial biogenesis and oxidative metabolism in brown adipose
tissue and muscle. In muscle, the increase of PGC1α expression stimulates an upregulation of FNDC5,
a membrane protein that is cleaved and secreted into the circulation as the myokine irisin [237]. FNDC5
cross the blood–brain barrier inducing BDNF expression in the hippocampus, in this way BDNF plays
a role in neurogenesis and reward-related learning and motivation [238]. Current research has also
shown that high intensity exercise increases peripheral lactate and BDNF levels; at the same time
lactate infusion at rest can increase peripheral and central BDNF levels. Lactate and BDNF can induce
neuroplasticity [239]. In addition, acute elevation of BDNF did not compensate for hypoxia-induced
cognition impairment [240].
Int. J. Mol. Sci. 2020, 21, 7777 12 of 29

The identification of exercise-related factors that have a direct or indirect effect on brain function
has the potential to highlight novel therapeutic targets for neurodegenerative diseases.

4. The Protective Role of BDNF on Neurodegeneration

Neurodegenerative diseases comprise a wide range of neurological diseases such as AD, PD,
Huntington’s disease, and amyotrophic lateral sclerosis (ALS), characterized by the deterioration and
then the Int.
death
J. Mol. of selective
Sci. 2020, 21, x FORnuclei of neurons in the brain or the spinal cord. They 12are
PEER REVIEW chronic and
of 30

progressive diseases, currently incurable

4. The Protective Role of BDNF on Neurodegeneration
and highly debilitating, causing a tremendous emotional
and economic burden on patients, their families, and society. AD, the most frequent among
Neurodegenerative diseases comprise a wide range of neurological diseases such as AD, PD,
neurodegenerative
Huntington’s disease,diseases, accounts for
and amyotrophic about
lateral 70%
sclerosis of characterized
(ALS), dementia cases all over the
by the deterioration andworld, that
is about 35 million people. It is estimated to cost more than 480 billion
then the death of selective nuclei of neurons in the brain or the spinal cord. They are chronic andeuros each year throughout the
progressive diseases, currently incurable and highly debilitating,
world (Sources: OMS, EBC (European Brain Council)). Currently, no pharmacological treatment is causing a tremendous emotional
availableand
to cureeconomic burden on patients, their families, and society. AD, the most frequent among
or even significantly slow down the course of neurodegenerative diseases. For these
neurodegenerative diseases, accounts for about 70% of dementia cases all over the world, that is about
reasons, experimental
35 million people.findings showing
It is estimated to costthat
morephysical exercise,
than 480 billion eurosexposure to an enriched
each year throughout the worldenvironment,
metabolic changes
(Sources: OMS, and
EBCnutritional
(European Brain and/or cognitive
Council)). Currently, intervention,
no pharmacological maytreatment
exert ais available
protective role on
to cure or eveneither
neurodegeneration significantly slow down
by delaying the theonset
courseand/or
of neurodegenerative
curbing thediseases.
course For thesedisease,
of the reasons, raise hope
experimental findings showing that physical exercise, exposure to an enriched environment,
that these new tools might be useful also in clinical practice. BDNF appears to be crucial or, in some
metabolic changes and nutritional and/or cognitive intervention, may exert a protective role on
cases even essential, to mediate
neurodegeneration the neuroprotective
either by delaying effects the
the onset and/or curbing of course
the above-mentioned environmental
of the disease, raise hope
stimuli (Figure 3). In particular, as discussed above, it is well established
that these new tools might be useful also in clinical practice. BDNF appears to be crucial or, in some that BDNF accounts for the
cases even essential, to mediate the neuroprotective effects of the
hippocampal adult neurogenesis, which, in turn, can be stimulated by a number of conditions such above-mentioned environmental
stimuli (Figure 3). In particular, as discussed above, it is well established that BDNF accounts for the
as physical exercise, enriched environment, hormonal balance (i.e., steroid hormones such a cortisol
hippocampal adult neurogenesis, which, in turn, can be stimulated by a number of conditions such
and testosterone)
as physical and nutritional
exercise, intervention
enriched environment, (i.e., fasting,
hormonal balance low-calorie intake, such
(i.e., steroid hormones low-carb diet, selective
a cortisol
nutrient intakes),
and testosterone)capable andof increasing
nutritional the BDNF
intervention level [241].
(i.e., fasting, low-calorie intake, low-carb diet, selective
nutrient intakes), capable of increasing the BDNF level [241].

Figure 3. The molecular mechanisms mediated by BDNF involved in depression, Alzheimer’s disease,
Theglioma.
Figure 3.and molecular mechanisms
External mediated
stimuli (stress, maternal by BDNF involved
deprivation, or lack of in depression,
activity) causing Alzheimer’s
epigenetic disease,
and glioma. External
regulation stimuli
processes (stress,
can induce maternal
a reduction deprivation,
in BDNF or lack
expression level and inofneuronal
activity) causing
activity. This epigenetic
regulation processes can induce a reduction in BDNF expression level and in neuronal activity.
Int. J. Mol. Sci. 2020, 21, 7777 13 of 29

This results in atrophy, neuronal death, and cognitive decline, which may contribute to depression or
Alzheimer’s disease. In these pathologies the BDNF/TrkB signaling, which activates the downstream Akt
and ERK signaling, is altered. Thus, such alterations cause an impairment of CREB signaling resulting
in BDNF downregulation. The alteration of phosphorylation (P) inhibits (red X) the transcriptional
machinery. In the mouse brain, environmental enrichment induces an increase of BDNF. BDNF, binding
the truncated form of TrkB receptor (TrkB.T1), signals directly to the Rho protein dissociation inhibitor
(GDI). The latter detaches from TrkB.T1 and binds to the small G protein RhoA, leading to an inhibition
of glioma cell migration. BDNF stimulates also indirectly the production of IL-15 in microglia, which in
turn stimulates the natural killer cells to produce IFN-γ. IFN-γ contributes to reducing glioma growth.

4.1. The Protective Role of BDNF on Alzheimer’s Disease

A reduced level of BDNF has been found in patients affected by neurodegenerative diseases
such as Parkinson’s, Huntington’s and Alzheimer’s disease as well as in mild cognitive impairment,
the latter being a prodromal stage of AD, characterized by a slight decline of cognitive abilities
including memory, thinking and judging skills [242–245]. In some instances, the levels of BDNF
even correlate with the severity of the diseases, pointing towards a pathogenetic link between BDNF
and AD [246]. Although there are some papers reporting an increase of BDNF in serum or in the
post-mortem brain, this might be due either to compensatory mechanisms or its release from immune
cells or pharmacological treatments known to raise BDNF (i.e., antidepressants) [241].
Recently, a very complex study explored the role of physical activity in a genetic mouse model of
AD. This study provided the most compelling evidence of the relationship between physical activity,
adult hippocampal neurogenesis, BDNF, and AD. This study elegantly confirms that adult hippocampal
neurogenesis plays a pivotal role in brain resilience to AD. They manipulated with pharmacological and
genetic tool neurogenesis as well as BDNF, clearly showing that physical exercise needs neurogenesis
to protect the brain from AD and that BDNF is essential for such a protection. In addition, it provides
evidence that adult hippocampal neurogenesis can counteract AD memory impairment, only in
combination with BDNF, whereas if neurogenesis is experimentally blocked, BDNF does not exert
beneficial effects. Finally, pharmacological increase of BDNF further ameliorates AD pathology [247].
Thus, agents that promote both BDNF signaling and neurogenesis might be the key to preventing or
curing AD. As far as metabolism is concerned, it has been shown that intermitting fasting, by causing
a transition from utilization of carbohydrate and glucose to a fatty acid and ketones source of energy
(refer to as “G-K shift”) generates a number of beneficial cognitive, metabolic, and cardiovagal effects.
BDNF is increased upon intermitting fasting and mediates at least part of these effects. Its increase
is stimulated by the ketone body, β-hydroxybutyrate that inhibits histone deacetylases that repress
BDNF promoters [248]. Recently, the role of BDNF and neuroprotection in the context of metabolism
and fasting has been nicely reviewed by Mattson et al. [6].

4.2. BDNF and Ras-ERK-CREB Signaling in Alzheimer’s Disease

BDNF, as also discussed above, causes the activation of the Ras-ERK signaling cascade leading
to the phosphorylation of CREB. Such a pathway exerts a well-known trophic and protective role on
neuronal cells both in vitro and in vivo in a variety of neurodegenerative models, including AD, PD,
and Huntington’s diseases. Nevertheless, it has become clear that the Ras-ERK pathway may also foster
neurodegeneration or hamper the action of neurotrophic factors when activated by noxious stimuli
as occurs for instance in PD and AD [249]. In particular, it has been shown in a number of different
cellular models such as primary cortical rat neurons, rat B103 neuroblastoma cells, and A1 mouse
mesencephalic cells, that APP and/or Aβ42 oligomer induces the activation of Ras-ERK and GSK-3
signaling, that, in turn, causes hyperphosphorylation of tau and APP at Thr668. The involvement of
these molecular events in the pathogenesis AD is corroborated by the finding that activation of Ras-ERK
and GSK-3 correlates with Aβ levels in the brain of AD patients [250,251]. Aberrant stimulation of
Ras-ERK signaling forces neurons to enter the cell cycle as shown by the expression and nuclear
accumulation of cyclin D1 and the subsequent G1/S progression. Since neurons lack functional cell
Int. J. Mol. Sci. 2020, 21, 7777 14 of 29

cycle machinery, these events lead to cell death (i.e., mitotic catastrophe) instead of cell division.
Interestingly, as clearly shown in the mouse model of familial AD APPswe/PS1∆E9 mice, although
ERK phosphorylation is enhanced compared to the wild type counterpart, it does not result in normal
CREB phosphorylation. The impairment in CREB signaling parallels to impairment in a number of
cognitive tests [252]. Therefore, in AD, BDNF downregulation is mediated by the impairment of CREB
signaling caused by amyloid β [253] (Figure 3).

5. BDNF and Brain Cancer: An Unexpected Role. An Oncogene or a Tumor Suppressor?

The role of BDNF and its cognate receptor TrkB in cancer, including brain cancer, has been
recognized for a long time [254]. In many types of cancers, BDNF and/or TrkB have been found
expressed or in some cases over-expressed [255]. This is not surprising since growth factors, including
neurotrophic factors, and their tyrosine kinase receptors have long been involved in tumors with
different cell-dependent mechanisms, fostering proliferation, enhancing anti-apoptotic signaling,
and making cells unresponsive to anti-proliferative stimuli [256]. The direct oncogenic activity of TrkB
might also be due to the crosstalk with EGF receptors that together with its ligand is well-known
to promote cell transformation. BDNF administration not only does phosphorylate TrkB but also
EGFR [257]. In line with these observations, it has been recently shown that BDNF produced by
glioblastoma (GBM) differentiated cells acts on GBM stem cells, fostering their growth through
paracrine signaling [258].
However, recently another study showed that exposing mice to an enriched environment is able to
decrease the growth of intracranial glioma, decreasing proliferation and invasion, and improving overall
survival. Such an effect is achieved by means of both indirect and direct mechanisms. The former acts
via natural killer cells of the innate immune system, whereas the latter utilizes BDNF stimulation of its
truncated receptor TrkB.T1 on glioma cancer cells. BDNF binding the TrkB.T1 receptor signals to the
Rho protein dissociation inhibitor (RhoGDI), the latter detaches from TrkB.T1 and binds to the small
G protein RhoA, leading to its inhibition. The authors found that an enriched environment causes the
synthesis of IL-15 and BDNF. When mice bearing the glioma and not housed in enriched environments
were infused with BDNF, they reduced tumor size and macrophage infiltration. Thus, showing that at
least in part, BDNF accounts for the oncolytic effect elicited by the enriched environment [259]. In a more
recent study, the same group delved deeper into the mechanisms, finding that enriched environment
changes glioma-associated myeloid cells. BDNF plays a central role by stimulating the production of
IL-15 in microglia, which in turn stimulates the natural killer cells to produce IFN-γ. Natural killer cells
were responsible for the switch to an oncolytic environment [260] (Figure 3).
Taken together, a scenario emerges where BDNF, acting on different cells is able to reorganize the
brain microenvironment in such a way that it becomes resilient to neurodegeneration or oncolytic for
tumors. In this regard, although supported by much more preliminary data, it seems that also other
compounds might share these properties [261,262].

6. Conclusions
In this review, we discussed the role of BDNF in neurogenesis, differentiation, survival, synaptic
plasticity, and transmission to reorganize the brain microenvironment. All BDNF gene products, such as
proBDNF, mature BDNF, and even the isolated proBDNF domain, are known to exert functional activity.
One of the most important features of BDNF is that it can act as a local, paracrine and/or autocrine factor,
on both pre-synaptic and post-synaptic target sites. Here, we presented the contribution of altered
BDNF signaling in the pathophysiology of brain diseases, including mental disorders (i.e., depression),
neurodegenerative diseases, (i.e., Alzheimer’s disease), and brain tumor (i.e., glioblastoma). BDNF is
one of the best-studied synaptic molecules that efficiently modify synaptic strength and it can act as a
mediator, modulator, or instructor of synaptic plasticity. In neurons, the cellular processes that regulate
the amount of both BDNF mRNA and protein, the changes in the efficiency of secretion, and transport
of BDNF protein may affect synaptic function and cell survival. BDNF is one of the most inspiring
Int. J. Mol. Sci. 2020, 21, 7777 15 of 29

molecules to better understand the disadvantageous synaptic learning underlying the etiology of
depression, accompanied by the decline in the rate of adult neurogenesis and in spine densities.
Furthermore, BDNF appears to exert a potent role in neuroprotection and/or brain regeneration
by modulating signaling pathways such Ras-ERK-CREB, thus rendering neuronal cells resilient to
neurodegeneration. Finally, BDNF appears to be crucial in the pathogenesis and development of
brain tumors such as glioblastoma by reorganizing its microenvironment. Thus, understanding the
physiologic and pathologic BDNF signaling and finding tools to modulate its expression (mRNA
and/or protein) is a prerequisite for a potential BDNF-based therapy.

Author Contributions: Original draft preparation, writing and editing, L.C.-D., L.S.; original draft preparation,
writing and review, F.V. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by program VALERE: VAnviteLli pEr la RicErca to L.C.D.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations
AD Alzheimer’s Disease
AP1 Activator Protein 1
BCL2 B-cell lymphoma 2
BDNF Brain-Derived Neurotrophic Factor
BHLHB2 Helix-loop-helix protein
CaMK Ca2+ /calmodulin-dependent protein kinase
cAMP/CRE Cyclic adenosine monophosphate calcium response element
CaREs Calcium-responsive elements
CREB CREB
Ctsb Myokine cathepsin B
CUMS Chronic Unpredicted Mild Stress model
DAG 1,2-diacylglycerol
ERK Extracellular signal-regulated kinase
GTP-ases guanosine triphosphate hydrolases
JNK c-Jun amino terminal kinase
IKK Multi-subunit IκB kinase
IkB Inhibitor of kB
L-VGCC L-type voltage gated calcium channel
LTP Long-Term Potentiation
MAPK Mitogen-activated protein kinase
MDD Major depressive disorder
Met Methionine
miRNAs microRNAs
MMP Matrix Metalloproteases
MPP 1-methyl-4-phenylpyridinium
NF-kB Nuclear Factor kappa-light-chain-enhancer of activated B cells
NMDA N-Methyl-D-Aspartate
NRAGE Neurotrophin receptor-interacting MAGE homologue
NRIF Neurotrophin receptor interacting factor
PD Parkinson’s disease
p75NTR p75 neurotrophin receptor
PI3K Phosphoinositide 3-kinases
PKC Protein kinase C
PLC Phospholipase C
Rho Ras homolog
Int. J. Mol. Sci. 2020, 21, 7777 16 of 29

ROCK Rho-associated protein kinase

SIRT1 Sirtuin 1
SNPs Polymorphism
SSRIs Serotonin reuptake inhibitor
TRAF6 Tumor necrosis factor receptor associated factor 6
TrkB Tropomycin receptor kinase B
Val Valine
VDCCs L-type voltage-dependent Ca2+ channels
Vps10p Vacuolar protein sorting 10 protein

References
1. Andreska, T.; Aufmkolk, S.; Sauer, M.; Blum, R. High abundance of BDNF within glutamatergic presynapses
of cultured hippocampal neurons. Front. Cell Neurosci. 2014, 8, 107. [CrossRef]
2. Clarke, L.E.; Liddelow, S.A.; Chakraborty, C.; Münch, A.E.; Heiman, M.; Barres, B.A. Normal aging induces
A1-like astrocyte reactivity. Proc. Natl. Acad. Sci. USA 2018, 115, E1896–E1905. [CrossRef]
3. Parkhurst, C.N.; Yang, G.; Ninan, I.; Savas, J.N.; Yates, J.R.; Lafaille, J.J.; Hempstead, B.L.; Littman, D.R.;
Gan, W.B. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic
factor. Cell 2013, 155, 1596–1609. [CrossRef]
4. Bartkowska, K.; Paquin, A.; Gauthier, A.S.; Kaplan, D.R.; Miller, F.D. Trk signaling regulates neural precursor
cell proliferation and differentiation during cortical development. Development 2007, 134, 4369–4380.
[CrossRef]
5. Vilar, M.; Mira, H. Regulation of Neurogenesis by Neurotrophins during Adulthood: Expected and
Unexpected Roles. Front. Neurosci. 2016, 10, 26. [CrossRef]
6. Mattson, M.P.; Moehl, K.; Ghena, N.; Schmaedick, M.; Cheng, A. Intermittent metabolic switching,
neuroplasticity and brain health. Nat. Rev. Neurosci. 2018, 19, 63–80. [CrossRef]
7. Numakawa, T.; Odaka, H.; Adachi, N. Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis
and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases. Int. J. Mol. Sci. 2018,
19, 3650. [CrossRef]
8. Loprinzi, P.D.; Day, S.; Deming, R. Acute Exercise Intensity and Memory Function: Evaluation of the
Transient Hypofrontality Hypothesis. Medicina (Kaunas) 2019, 55, 445. [CrossRef]
9. Fabel, K.; Wolf, S.A.; Ehninger, D.; Babu, H.; Leal-Galicia, P.; Kempermann, G. Additive effects of physical
exercise and environmental enrichment on adult hippocampal neurogenesis in mice. Front. Neurosci. 2009,
3, 50. [CrossRef]
10. Knaepen, K.; Goekint, M.; Heyman, E.M.; Meeusen, R. Neuroplasticity-exercise-induced response of
peripheral brain-derived neurotrophic factor: A systematic review of experimental studies in human subjects.
Sports Med. 2010, 40, 765–801. [CrossRef]
11. Szuhany, K.L.; Bugatti, M.; Otto, M.W. A meta-analytic review of the effects of exercise on brain-derived
neurotrophic factor. J. Psychiatr. Res. 2015, 60, 56–64. [CrossRef] [PubMed]
12. van Praag, H.; Shubert, T.; Zhao, C.; Gage, F.H. Exercise enhances learning and hippocampal neurogenesis in
aged mice. J. Neurosci. 2005, 25, 8680–8685. [CrossRef] [PubMed]
13. Tuon, T.; Souza, P.S.; Santos, M.F.; Pereira, F.T.; Pedroso, G.S.; Luciano, T.F.; De Souza, C.T.; Dutra, R.C.;
Silveira, P.C.; Pinho, R.A. Physical Training Regulates Mitochondrial Parameters and Neuroinflammatory
Mechanisms in an Experimental Model of Parkinson’s Disease. Oxid. Med. Cell. Longev. 2015, 2015, 261809.
[CrossRef] [PubMed]
14. Vilela, T.C.; Muller, A.P.; Damiani, A.P.; Macan, T.P.; da Silva, S.; Canteiro, P.B.; de Sena Casagrande, A.;
Pedroso, G.D.S.; Nesi, R.T.; de Andrade, V.M.; et al. Strength and Aerobic Exercises Improve Spatial Memory
in Aging Rats Through Stimulating Distinct Neuroplasticity Mechanisms. Mol. Neurobiol. 2017, 54, 7928–7937.
[CrossRef]
15. Itami, C.; Kimura, F.; Kohno, T.; Matsuoka, M.; Ichikawa, M.; Tsumoto, T.; Nakamura, S. Brain-derived
neurotrophic factor-dependent unmasking of "silent" synapses in the developing mouse barrel cortex.
Proc. Natl. Acad. Sci. USA 2003, 100, 13069–13074. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 7777 17 of 29

16. Edelmann, E.; Lessmann, V.; Brigadski, T. Pre-and postsynaptic twists in BDNF secretion and action in
synaptic plasticity. Neuropharmacology 2014, 76 Pt C, 610–627. [CrossRef]
17. Nakahashi, T.; Fujimura, H.; Altar, C.A.; Li, J.; Kambayashi, J.; Tandon, N.N.; Sun, B. Vascular endothelial
cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett. 2000, 470, 113–117. [CrossRef]
18. Wang, H.; Ward, N.; Boswell, M.; Katz, D.M. Secretion of brain-derived neurotrophic factor from brain
microvascular endothelial cells. Eur. J. Neurosci. 2006, 23, 1665–1670. [CrossRef]
19. Pius-Sadowska, E.; Machaliński, B. BDNF-A key player in cardiovascular system. J. Mol. Cell. Cardiol. 2017,
110, 54–60. [CrossRef]
20. Anders, Q.S.; Ferreira, L.V.B.; Rodrigues, L.C.M.; Nakamura-Palacios, E.M. BDNF mRNA Expression in
Leukocytes and Frontal Cortex Function in Drug Use Disorder. Front. Psychiatry 2020, 11, 469. [CrossRef]
21. Chacón-Fernández, P.; Säuberli, K.; Colzani, M.; Moreau, T.; Ghevaert, C.; Barde, Y.A. Brain-derived
Neurotrophic Factor in Megakaryocytes. J. Biol. Chem. 2016, 291, 9872–9881. [CrossRef] [PubMed]
22. Amadio, P.; Sandrini, L.; Ieraci, A.; Tremoli, E.; Barbieri, S.S. Effect of Clotting Duration and Temperature on
BDNF Measurement in Human Serum. Int. J. Mol. Sci. 2017, 18, 1987. [CrossRef] [PubMed]
23. Meek, T.H.; Wisse, B.E.; Thaler, J.P.; Guyenet, S.J.; Matsen, M.E.; Fischer, J.D.; Taborsky, G.J.; Schwartz, M.W.;
Morton, G.J. BDNF action in the brain attenuates diabetic hyperglycemia via insulin-independent inhibition
of hepatic glucose production. Diabetes 2013, 62, 1512–1518. [CrossRef] [PubMed]
24. Marosi, K.; Mattson, M.P. BDNF mediates adaptive brain and body responses to energetic challenges.
Trends Endocrinol. Metab. 2014, 25, 89–98. [CrossRef] [PubMed]
25. Delezie, J.; Weihrauch, M.; Maier, G.; Tejero, R.; Ham, D.J.; Gill, J.F.; Karrer-Cardel, B.; Rüegg, M.A.;
Tabares, L.; Handschin, C. BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle.
Proc. Natl. Acad. Sci. USA 2019, 116, 16111–16120. [CrossRef]
26. Tettamanti, G.; Cattaneo, A.G.; Gornati, R.; de Eguileor, M.; Bernardini, G.; Binelli, G. Phylogenesis of
brain-derived neurotrophic factor (BDNF) in vertebrates. Gene 2010, 450, 85–93. [CrossRef]
27. Metsis, M.; Timmusk, T.; Arenas, E.; Persson, H. Differential usage of multiple brain-derived neurotrophic
factor promoters in the rat brain following neuronal activation. Proc. Natl. Acad. Sci. USA 1993, 90, 8802–8806.
[CrossRef]
28. Timmusk, T.; Lendahl, U.; Funakoshi, H.; Arenas, E.; Persson, H.; Metsis, M. Identification of brain-derived
neurotrophic factor promoter regions mediating tissue-specific, axotomy-, and neuronal activity-induced
expression in transgenic mice. J. Cell Biol. 1995, 128, 185–199. [CrossRef]
29. Timmusk, T.; Palm, K.; Metsis, M.; Reintam, T.; Paalme, V.; Saarma, M.; Persson, H. Multiple promoters
direct tissue-specific expression of the rat BDNF gene. Neuron 1993, 10, 475–489. [CrossRef]
30. Vashishta, A.; Habas, A.; Pruunsild, P.; Zheng, J.J.; Timmusk, T.; Hetman, M. Nuclear factor of activated
T-cells isoform c4 (NFATc4/NFAT3) as a mediator of antiapoptotic transcription in NMDA receptor-stimulated
cortical neurons. J. Neurosci. 2009, 29, 15331–15340. [CrossRef]
31. Volpicelli, F.; Caiazzo, M.; Greco, D.; Consales, C.; Leone, L.; Perrone-Capano, C.; Colucci D’Amato, L.;
di Porzio, U. Bdnf gene is a downstream target of Nurr1 transcription factor in rat midbrain neurons in vitro.
J. Neurochem. 2007, 102, 441–453. [CrossRef] [PubMed]
32. Aid, T.; Kazantseva, A.; Piirsoo, M.; Palm, K.; Timmusk, T. Mouse and rat BDNF gene structure and expression
revisited. J. Neurosci. Res. 2007, 85, 525–535. [CrossRef] [PubMed]
33. Pruunsild, P.; Kazantseva, A.; Aid, T.; Palm, K.; Timmusk, T. Dissecting the human BDNF locus: Bidirectional
transcription, complex splicing, and multiple promoters. Genomics 2007, 90, 397–406. [CrossRef] [PubMed]
34. Paoletti, P.; Bellone, C.; Zhou, Q. NMDA receptor subunit diversity: Impact on receptor properties, synaptic
plasticity and disease. Nat. Rev. Neurosci. 2013, 14, 383–400. [CrossRef] [PubMed]
35. Simms, B.A.; Zamponi, G.W. Neuronal voltage-gated calcium channels: Structure, function, and dysfunction.
Neuron 2014, 82, 24–45. [CrossRef]
36. Shieh, P.B.; Hu, S.C.; Bobb, K.; Timmusk, T.; Ghosh, A. Identification of a signaling pathway involved in
calcium regulation of BDNF expression. Neuron 1998, 20, 727–740. [CrossRef]
37. Tao, X.; Finkbeiner, S.; Arnold, D.B.; Shaywitz, A.J.; Greenberg, M.E. Ca2+ influx regulates BDNF transcription
by a CREB family transcription factor-dependent mechanism. Neuron 1998, 20, 709–726. [CrossRef]
38. Tabuchi, A.; Sakaya, H.; Kisukeda, T.; Fushiki, H.; Tsuda, M. Involvement of an upstream stimulatory factor
as well as cAMP-responsive element-binding protein in the activation of brain-derived neurotrophic factor
gene promoter I. J. Biol. Chem. 2002, 277, 35920–35931. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 7777 18 of 29

39. Pruunsild, P.; Sepp, M.; Orav, E.; Koppel, I.; Timmusk, T. Identification of cis-elements and transcription
factors regulating neuronal activity-dependent transcription of human BDNF gene. J. Neurosci. 2011,
31, 3295–3308. [CrossRef]
40. Tao, X.; West, A.E.; Chen, W.G.; Corfas, G.; Greenberg, M.E. A calcium-responsive transcription factor, CaRF,
that regulates neuronal activity-dependent expression of BDNF. Neuron 2002, 33, 383–395. [CrossRef]
41. Zheng, F.; Wang, H. NMDA-mediated and self-induced bdnf exon IV transcriptions are differentially
regulated in cultured cortical neurons. Neurochem. Int. 2009, 54, 385–392. [CrossRef] [PubMed]
42. Lipsky, R.H.; Xu, K.; Zhu, D.; Kelly, C.; Terhakopian, A.; Novelli, A.; Marini, A.M. Nuclear factor kappaB
is a critical determinant in N-methyl-D-aspartate receptor-mediated neuroprotection. J. Neurochem. 2001,
78, 254–264. [CrossRef] [PubMed]
43. Zheng, F.; Zhou, X.; Moon, C.; Wang, H. Regulation of brain-derived neurotrophic factor expression in
neurons. Int. J. Physiol. Pathophysiol. Pharmacol. 2012, 4, 188–200. [PubMed]
44. Jiang, X.; Tian, F.; Du, Y.; Copeland, N.G.; Jenkins, N.A.; Tessarollo, L.; Wu, X.; Pan, H.; Hu, X.Z.; Xu, K.; et al.
BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability. J. Neurosci. 2008, 28, 1118–1130.
[CrossRef]
45. Sakata, K.; Woo, N.H.; Martinowich, K.; Greene, J.S.; Schloesser, R.J.; Shen, L.; Lu, B. Critical role of promoter
IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex.
Proc. Natl. Acad. Sci. USA 2009, 106, 5942–5947. [CrossRef]
46. Keller, S.; Sarchiapone, M.; Zarrilli, F.; Videtic, A.; Ferraro, A.; Carli, V.; Sacchetti, S.; Lembo, F.; Angiolillo, A.;
Jovanovic, N.; et al. Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Arch.
Gen. Psychiatry 2010, 67, 258–267. [CrossRef]
47. Tadić, A.; Müller-Engling, L.; Schlicht, K.F.; Kotsiari, A.; Dreimüller, N.; Kleimann, A.; Bleich, S.; Lieb, K.;
Frieling, H. Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant
response in major depression. Mol. Psychiatry 2014, 19, 281–283. [CrossRef]
48. Lieb, K.; Dreimüller, N.; Wagner, S.; Schlicht, K.; Falter, T.; Neyazi, A.; Müller-Engling, L.; Bleich, S.; Tadić, A.;
Frieling, H. BDNF Plasma Levels and BDNF Exon IV Promoter Methylation as Predictors for Antidepressant
Treatment Response. Front. Psychiatry 2018, 9, 511. [CrossRef]
49. Sakata, K.; Duke, S.M. Lack of BDNF expression through promoter IV disturbs expression of monoamine
genes in the frontal cortex and hippocampus. Neuroscience 2014, 260, 265–275. [CrossRef]
50. Hill, J.L.; Hardy, N.F.; Jimenez, D.V.; Maynard, K.R.; Kardian, A.S.; Pollock, C.J.; Schloesser, R.J.;
Martinowich, K. Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep,
sensory information processing and fear regulation. Transl. Psychiatry 2016, 6, e873. [CrossRef]
51. Volpicelli, F.; Speranza, L.; Pulcrano, S.; De Gregorio, R.; Crispino, M.; De Sanctis, C.; Leopoldo, M.;
Lacivita, E.; di Porzio, U.; Bellenchi, G.C.; et al. The microRNA-29a Modulates Serotonin 5-HT7 Receptor
Expression and Its Effects on Hippocampal Neuronal Morphology. Mol. Neurobiol. 2019, 56, 8617–8627.
[CrossRef] [PubMed]
52. De Gregorio, R.; Pulcrano, S.; De Sanctis, C.; Volpicelli, F.; Guatteo, E.; von Oerthel, L.; Latagliata, E.C.;
Esposito, R.; Piscitelli, R.M.; Perrone-Capano, C.; et al. miR-34b/c Regulates Wnt1 and Enhances
Mesencephalic Dopaminergic Neuron Differentiation. Stem Cell Rep. 2018, 10, 1237–1250. [CrossRef]
[PubMed]
53. McNeill, E.; Van Vactor, D. MicroRNAs shape the neuronal landscape. Neuron 2012, 75, 363–379. [CrossRef]
[PubMed]
54. Keifer, J.; Zheng, Z.; Ambigapathy, G. A MicroRNA-BDNF Negative Feedback Signaling Loop in Brain:
Implications for Alzheimer0 s Disease. Microrna 2015, 4, 101–108. [CrossRef] [PubMed]
55. Khani-Habibabadi, F.; Askari, S.; Zahiri, J.; Javan, M.; Behmanesh, M. Novel BDNF-regulatory microRNAs
in neurodegenerative disorders pathogenesis: An in silico study. Comput. Biol. Chem. 2019, 83, 107153.
[CrossRef] [PubMed]
56. Schratt, G.M.; Tuebing, F.; Nigh, E.A.; Kane, C.G.; Sabatini, M.E.; Kiebler, M.; Greenberg, M.E. A brain-specific
microRNA regulates dendritic spine development. Nature 2006, 439, 283–289. [CrossRef]
57. Baby, N.; Alagappan, N.; Dheen, S.T.; Sajikumar, S. MicroRNA-134-5p inhibition rescues long-term plasticity
and synaptic tagging/capture in an Aβ(1-42)-induced model of Alzheimer’s disease. Aging Cell 2020,
19, e13046. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 7777 19 of 29

58. Gao, J.; Wang, W.Y.; Mao, Y.W.; Gräff, J.; Guan, J.S.; Pan, L.; Mak, G.; Kim, D.; Su, S.C.; Tsai, L.H. A novel
pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 2010, 466, 1105–1109. [CrossRef]
59. Shen, J.; Xu, L.; Qu, C.; Sun, H.; Zhang, J. Resveratrol prevents cognitive deficits induced by chronic
unpredictable mild stress: Sirt1/miR-134 signalling pathway regulates CREB/BDNF expression in
hippocampus in vivo and in vitro. Behav. Brain Res. 2018, 349, 1–7. [CrossRef]
60. Xin, C.; Xia, J.; Liu, Y.; Zhang, Y. MicroRNA-202-3p Targets Brain-Derived Neurotrophic Factor and Is
Involved in Depression-Like Behaviors. Neuropsychiatr. Dis. Treat. 2020, 16, 1073–1083. [CrossRef]
61. Yang, C.R.; Zhang, X.Y.; Liu, Y.; Du, J.Y.; Liang, R.; Yu, M.; Zhang, F.Q.; Mu, X.F.; Li, F.; Zhou, L.; et al.
Antidepressant Drugs Correct the Imbalance Between proBDNF/p75NTR/Sortilin and Mature BDNF/TrkB in
the Brain of Mice with Chronic Stress. Neurotox. Res. 2020, 37, 171–182. [CrossRef] [PubMed]
62. You, Y.H.; Qin, Z.Q.; Zhang, H.L.; Yuan, Z.H.; Yu, X. MicroRNA-153 promotes brain-derived neurotrophic
factor and hippocampal neuron proliferation to alleviate autism symptoms through inhibition of JAK-STAT
pathway by LEPR. Biosci. Rep. 2019, 39. [CrossRef]
63. Rostamian Delavar, M.; Baghi, M.; Safaeinejad, Z.; Kiani-Esfahani, A.; Ghaedi, K.; Nasr-Esfahani, M.H.
Differential expression of miR-34a, miR-141, and miR-9 in MPP+-treated differentiated PC12 cells as a model
of Parkinson0 s disease. Gene 2018, 662, 54–65. [CrossRef] [PubMed]
64. Zhao, X.; Shu, F.; Wang, X.; Wang, F.; Wu, L.; Li, L.; Lv, H. Inhibition of microRNA-375 ameliorated
ketamine-induced neurotoxicity in human embryonic stem cell derived neurons. Eur. J. Pharmacol. 2019,
844, 56–64. [CrossRef] [PubMed]
65. Jiang, J.D.; Zheng, X.C.; Huang, F.Y.; Gao, F.; You, M.Z.; Zheng, T. MicroRNA-107 regulates anesthesia-induced
neural injury in embryonic stem cell derived neurons. IUBMB Life 2019, 71, 20–27. [CrossRef] [PubMed]
66. Barde, Y.A.; Edgar, D.; Thoenen, H. Purification of a new neurotrophic factor from mammalian brain. EMBO
J. 1982, 1, 549–553. [CrossRef]
67. Foltran, R.B.; Diaz, S.L. BDNF isoforms: A round trip ticket between neurogenesis and serotonin? J. Neurochem.
2016, 138, 204–221. [CrossRef]
68. Mizui, T.; Ishikawa, Y.; Kumanogoh, H.; Kojima, M. Neurobiological actions by three distinct subtypes of
brain-derived neurotrophic factor: Multi-ligand model of growth factor signaling. Pharmacol. Res. 2016, 105,
93–98. [CrossRef]
69. Lu, J.; Wu, Y.; Sousa, N.; Almeida, O.F. SMAD pathway mediation of BDNF and TGF beta 2 regulation
of proliferation and differentiation of hippocampal granule neurons. Development 2005, 132, 3231–3242.
[CrossRef]
70. Kowiański, P.; Lietzau, G.; Czuba, E.; Waśkow, M.; Steliga, A.; Moryś, J. BDNF: A Key Factor with Multipotent
Impact on Brain Signaling and Synaptic Plasticity. Cell Mol. Neurobiol. 2018, 38, 579–593. [CrossRef]
71. Pang, P.T.; Teng, H.K.; Zaitsev, E.; Woo, N.T.; Sakata, K.; Zhen, S.; Teng, K.K.; Yung, W.H.; Hempstead, B.L.;
Lu, B. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 2004,
306, 487–491. [CrossRef]
72. Mizoguchi, H.; Nakade, J.; Tachibana, M.; Ibi, D.; Someya, E.; Koike, H.; Kamei, H.; Nabeshima, T.;
Itohara, S.; Takuma, K.; et al. Matrix metalloproteinase-9 contributes to kindled seizure development in
pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. J. Neurosci.
2011, 31, 12963–12971. [CrossRef]
73. Vafadari, B.; Salamian, A.; Kaczmarek, L. MMP-9 in translation: From molecule to brain physiology,
pathology, and therapy. J. Neurochem. 2016, 139 (Suppl. S2), 91–114. [CrossRef]
74. Mowla, S.J.; Farhadi, H.F.; Pareek, S.; Atwal, J.K.; Morris, S.J.; Seidah, N.G.; Murphy, R.A. Biosynthesis
and post-translational processing of the precursor to brain-derived neurotrophic factor. J. Biol. Chem. 2001,
276, 12660–12666. [CrossRef] [PubMed]
75. Conner, J.M.; Lauterborn, J.C.; Yan, Q.; Gall, C.M.; Varon, S. Distribution of brain-derived neurotrophic
factor (BDNF) protein and mRNA in the normal adult rat CNS: Evidence for anterograde axonal transport.
J. Neurosci. 1997, 17, 2295–2313. [CrossRef]
76. Dieni, S.; Matsumoto, T.; Dekkers, M.; Rauskolb, S.; Ionescu, M.S.; Deogracias, R.; Gundelfinger, E.D.;
Kojima, M.; Nestel, S.; Frotscher, M.; et al. BDNF and its pro-peptide are stored in presynaptic dense core
vesicles in brain neurons. J. Cell Biol. 2012, 196, 775–788. [CrossRef] [PubMed]
77. Yang, J.; Siao, C.J.; Nagappan, G.; Marinic, T.; Jing, D.; McGrath, K.; Chen, Z.Y.; Mark, W.; Tessarollo, L.;
Lee, F.S.; et al. Neuronal release of proBDNF. Nat. Neurosci. 2009, 12, 113–115. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 7777 20 of 29

78. Yang, J.L.; Lin, Y.T.; Chuang, P.C.; Bohr, V.A.; Mattson, M.P. BDNF and exercise enhance neuronal DNA repair
by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1. Neuromolecular Med.
2014, 16, 161–174. [CrossRef]
79. Du, J.; Feng, L.; Yang, F.; Lu, B. Activity- and Ca(2+)-dependent modulation of surface expression of
brain-derived neurotrophic factor receptors in hippocampal neurons. J. Cell Biol. 2000, 150, 1423–1434.
[CrossRef] [PubMed]
80. Meyer-Franke, A.; Wilkinson, G.A.; Kruttgen, A.; Hu, M.; Munro, E.; Hanson, M.G.; Reichardt, L.F.;
Barres, B.A. Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS
neurons. Neuron 1998, 21, 681–693. [CrossRef]
81. Deinhardt, K.; Chao, M.V. Shaping neurons: Long and short range effects of mature and proBDNF signalling
upon neuronal structure. Neuropharmacology 2014, 76 Pt C, 603–609. [CrossRef]
82. Anastasia, A.; Deinhardt, K.; Chao, M.V.; Will, N.E.; Irmady, K.; Lee, F.S.; Hempstead, B.L.; Bracken, C.
Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction.
Nat. Commun. 2013, 4, 2490. [CrossRef]
83. Teng, H.K.; Teng, K.K.; Lee, R.; Wright, S.; Tevar, S.; Almeida, R.D.; Kermani, P.; Torkin, R.; Chen, Z.Y.;
Lee, F.S.; et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and
sortilin. J. Neurosci. 2005, 25, 5455–5463. [CrossRef] [PubMed]
84. Roux, P.P.; Colicos, M.A.; Barker, P.A.; Kennedy, T.E. p75 neurotrophin receptor expression is induced in
apoptotic neurons after seizure. J. Neurosci. 1999, 19, 6887–6896. [CrossRef] [PubMed]
85. Reichardt, L.F. Neurotrophin-regulated signalling pathways. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2006,
361, 1545–1564. [CrossRef]
86. Kaplan, D.R.; Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol.
2000, 10, 381–391. [CrossRef]
87. Gonzalez, A.; Moya-Alvarado, G.; Gonzalez-Billaut, C.; Bronfman, F.C. Cellular and molecular mechanisms
regulating neuronal growth by brain-derived neurotrophic factor. Cytoskeleton (Hoboken) 2016, 73, 612–628.
[CrossRef]
88. Huang, E.J.; Reichardt, L.F. Trk receptors: Roles in neuronal signal transduction. Annu. Rev. Biochem. 2003,
72, 609–642. [CrossRef]
89. Minichiello, L. TrkB signalling pathways in LTP and learning. Nat. Rev. Neurosci. 2009, 10, 850–860.
[CrossRef]
90. Patel, A.V.; Krimm, R.F. BDNF is required for the survival of differentiated geniculate ganglion neurons. Dev.
Biol. 2010, 340, 419–429. [CrossRef]
91. Chen, J.; Shehadah, A.; Pal, A.; Zacharek, A.; Cui, X.; Cui, Y.; Roberts, C.; Lu, M.; Zeitlin, A.; Hariri, R.;
et al. Neuroprotective effect of human placenta-derived cell treatment of stroke in rats. Cell Transplant. 2013,
22, 871–879. [CrossRef] [PubMed]
92. Wu, Y.; Wang, R.; Wang, Y.; Gao, J.; Feng, L.; Yang, Z. Distinct Impacts of Fullerene on Cognitive Functions of
Dementia vs. Non-dementia Mice. Neurotox. Res. 2019, 36, 736–745. [CrossRef] [PubMed]
93. Gorski, J.A.; Zeiler, S.R.; Tamowski, S.; Jones, K.R. Brain-derived neurotrophic factor is required for the
maintenance of cortical dendrites. J. Neurosci. 2003, 23, 6856–6865. [CrossRef] [PubMed]
94. Kwon, M.; Fernández, J.R.; Zegarek, G.F.; Lo, S.B.; Firestein, B.L. BDNF-promoted increases in proximal
dendrites occur via CREB-dependent transcriptional regulation of cypin. J. Neurosci. 2011, 31, 9735–9745.
[CrossRef]
95. Orefice, L.L.; Waterhouse, E.G.; Partridge, J.G.; Lalchandani, R.R.; Vicini, S.; Xu, B. Distinct roles for
somatically and dendritically synthesized brain-derived neurotrophic factor in morphogenesis of dendritic
spines. J. Neurosci. 2013, 33, 11618–11632. [CrossRef]
96. Zagrebelsky, M.; Tacke, C.; Korte, M. BDNF signaling during the lifetime of dendritic spines. Cell Tissue
Res. 2020. [CrossRef]
97. Yoshii, A.; Constantine-Paton, M. Postsynaptic localization of PSD-95 is regulated by all three pathways
downstream of TrkB signaling. Front. Synaptic Neurosci. 2014, 6, 6. [CrossRef]
98. Chen, S.D.; Wu, C.L.; Hwang, W.C.; Yang, D.I. More Insight into BDNF against Neurodegeneration:
Anti-Apoptosis, Anti-Oxidation, and Suppression of Autophagy. Int. J. Mol. Sci. 2017, 18, 545. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 7777 21 of 29

99. Opazo, P.; Watabe, A.M.; Grant, S.G.; O’Dell, T.J. Phosphatidylinositol 3-kinase regulates the induction of
long-term potentiation through extracellular signal-related kinase-independent mechanisms. J. Neurosci.
2003, 23, 3679–3688. [CrossRef]
100. Leal, G.; Bramham, C.R.; Duarte, C.B. BDNF and Hippocampal Synaptic Plasticity. Vitam. Horm. 2017,
104, 153–195. [CrossRef]
101. Baydyuk, M.; Xu, B. BDNF signaling and survival of striatal neurons. Front. Cell. Neurosci. 2014, 8, 254.
[CrossRef]
102. Waterhouse, E.G.; An, J.J.; Orefice, L.L.; Baydyuk, M.; Liao, G.Y.; Zheng, K.; Lu, B.; Xu, B. BDNF promotes
differentiation and maturation of adult-born neurons through GABAergic transmission. J. Neurosci. 2012, 32,
14318–14330. [CrossRef] [PubMed]
103. Park, H.; Poo, M.M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci.
2013, 14, 7–23. [CrossRef]
104. Jaworski, J.; Spangler, S.; Seeburg, D.P.; Hoogenraad, C.C.; Sheng, M. Control of dendritic arborization by the
phosphoinositide-3’-kinase-Akt-mammalian target of rapamycin pathway. J. Neurosci. 2005, 25, 11300–11312.
[CrossRef] [PubMed]
105. Kumar, V.; Zhang, M.X.; Swank, M.W.; Kunz, J.; Wu, G.Y. Regulation of dendritic morphogenesis by
Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J. Neurosci. 2005, 25, 11288–11299. [CrossRef]
[PubMed]
106. Finkbeiner, S.; Tavazoie, S.F.; Maloratsky, A.; Jacobs, K.M.; Harris, K.M.; Greenberg, M.E. CREB: A major
mediator of neuronal neurotrophin responses. Neuron 1997, 19, 1031–1047. [CrossRef]
107. Xing, J.; Kornhauser, J.M.; Xia, Z.; Thiele, E.A.; Greenberg, M.E. Nerve growth factor activates extracellular
signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133
phosphorylation. Mol. Cell. Biol. 1998, 18, 1946–1955. [CrossRef]
108. Segal, M.; Kreher, U.; Greenberger, V.; Braun, K. Is fragile X mental retardation protein involved in
activity-induced plasticity of dendritic spines? Brain Res. 2003, 972, 9–15. [CrossRef]
109. Petryshen, T.L.; Sabeti, P.C.; Aldinger, K.A.; Fry, B.; Fan, J.B.; Schaffner, S.F.; Waggoner, S.G.; Tahl, A.R.;
Sklar, P. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol. Psychiatry
2010, 15, 810–815. [CrossRef]
110. Momose, Y.; Murata, M.; Kobayashi, K.; Tachikawa, M.; Nakabayashi, Y.; Kanazawa, I.; Toda, T. Association
studies of multiple candidate genes for Parkinson’s disease using single nucleotide polymorphisms.
Ann. Neurol. 2002, 51, 133–136. [CrossRef]
111. Ventriglia, M.; Bocchio Chiavetto, L.; Benussi, L.; Binetti, G.; Zanetti, O.; Riva, M.A.; Gennarelli, M.
Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer’s disease. Mol. Psychiatry
2002, 7, 136–137. [CrossRef]
112. Egan, M.F.; Kojima, M.; Callicott, J.H.; Goldberg, T.E.; Kolachana, B.S.; Bertolino, A.; Zaitsev, E.; Gold, B.;
Goldman, D.; Dean, M.; et al. The BDNF val66met polymorphism affects activity-dependent secretion of
BDNF and human memory and hippocampal function. Cell 2003, 112, 257–269. [CrossRef]
113. Chen, Z.Y.; Patel, P.D.; Sant, G.; Meng, C.X.; Teng, K.K.; Hempstead, B.L.; Lee, F.S. Variant brain-derived
neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of
wild-type BDNF in neurosecretory cells and cortical neurons. J. Neurosci. 2004, 24, 4401–4411. [CrossRef]
[PubMed]
114. Chiaruttini, C.; Vicario, A.; Li, Z.; Baj, G.; Braiuca, P.; Wu, Y.; Lee, F.S.; Gardossi, L.; Baraban, J.M.; Tongiorgi, E.
Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation.
Proc. Natl. Acad. Sci. USA 2009, 106, 16481–16486. [CrossRef] [PubMed]
115. Tsai, S.J. Salivary gland low-intensity pulsed ultrasound (LIPUS) stimulation as a potential treatment for
various BDNF-implicated neuropsychiatric disorders. Med. Hypotheses 2020, 137, 109560. [CrossRef]
[PubMed]
116. Lin, C.C.; Huang, T.L. Brain-derived neurotrophic factor and mental disorders. Biomed. J. 2020, 43, 134–142.
[CrossRef] [PubMed]
117. Di Lazzaro, V.; Pellegrino, G.; Di Pino, G.; Corbetto, M.; Ranieri, F.; Brunelli, N.; Paolucci, M.; Bucossi, S.;
Ventriglia, M.C.; Brown, P.; et al. Val66Met BDNF gene polymorphism influences human motor cortex
plasticity in acute stroke. Brain Stimul. 2015, 8, 92–96. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 7777 22 of 29

118. Morin-Moncet, O.; Latulipe-Loiselle, A.; Therrien-Blanchet, J.M.; Theoret, H. BDNF Val66Met polymorphism
is associated with altered activity-dependent modulation of short-interval intracortical inhibition in bilateral
M1. PLoS ONE 2018, 13, e0197505. [CrossRef]
119. Hashimoto, T.; Fukui, K.; Takeuchi, H.; Yokota, S.; Kikuchi, Y.; Tomita, H.; Taki, Y.; Kawashima, R. Effects
of the BDNF Val66Met Polymorphism on Gray Matter Volume in Typically Developing Children and
Adolescents. Cereb. Cortex 2016, 26, 1795–1803. [CrossRef]
120. Meng, W.D.; Sun, S.J.; Yang, J.; Chu, R.X.; Tu, W.; Liu, Q. Elevated Serum Brain-Derived Neurotrophic
Factor (BDNF) but not BDNF Gene Val66Met Polymorphism Is Associated with Autism Spectrum Disorders.
Mol. Neurobiol. 2017, 54, 1167–1172. [CrossRef]
121. Montag, C.; Basten, U.; Stelzel, C.; Fiebach, C.J.; Reuter, M. The BDNF Val66Met polymorphism and anxiety:
Support for animal knock-in studies from a genetic association study in humans. Psychiatry Res. 2010,
179, 86–90. [CrossRef] [PubMed]
122. Park, C.H.; Kim, J.; Namgung, E.; Lee, D.W.; Kim, G.H.; Kim, M.; Kim, N.; Kim, T.D.; Kim, S.; Lyoo, I.K.; et al.
The BDNF Val66Met Polymorphism Affects the Vulnerability of the Brain Structural Network. Front. Hum.
Neurosci. 2017, 11, 400. [CrossRef] [PubMed]
123. Hariri, A.R.; Goldberg, T.E.; Mattay, V.S.; Kolachana, B.S.; Callicott, J.H.; Egan, M.F.; Weinberger, D.R.
Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal
activity and predicts memory performance. J. Neurosci. 2003, 23, 6690–6694. [CrossRef] [PubMed]
124. Pezawas, L.; Verchinski, B.A.; Mattay, V.S.; Callicott, J.H.; Kolachana, B.S.; Straub, R.E.; Egan, M.F.;
Meyer-Lindenberg, A.; Weinberger, D.R. The brain-derived neurotrophic factor val66met polymorphism and
variation in human cortical morphology. J. Neurosci. 2004, 24, 10099–10102. [CrossRef] [PubMed]
125. Ho, B.C.; Milev, P.; O’Leary, D.S.; Librant, A.; Andreasen, N.C.; Wassink, T.H. Cognitive and magnetic
resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene
polymorphism in patients with schizophrenia and healthy volunteers. Arch. Gen. Psychiatry 2006, 63, 731–740.
[CrossRef] [PubMed]
126. Montag, C.; Weber, B.; Fliessbach, K.; Elger, C.; Reuter, M. The BDNF Val66Met polymorphism impacts
parahippocampal and amygdala volume in healthy humans: Incremental support for a genetic risk factor
for depression. Psychol. Med. 2009, 39, 1831–1839. [CrossRef] [PubMed]
127. Xia, H.; Du, X.; Yin, G.; Zhang, Y.; Li, X.; Cai, J.; Huang, X.; Ning, Y.; Soares, J.C.; Wu, F.; et al. Effects of
smoking on cognition and BDNF levels in a male Chinese population: Relationship with BDNF Val66Met
polymorphism. Sci. Rep. 2019, 9, 217. [CrossRef]
128. Altmann, V.; Schumacher-Schuh, A.F.; Rieck, M.; Callegari-Jacques, S.M.; Rieder, C.R.; Hutz, M.H. Val66Met
BDNF polymorphism is associated with Parkinson’s disease cognitive impairment. Neurosci. Lett. 2016,
615, 88–91. [CrossRef]
129. Wang, Q.; Liu, J.; Guo, Y.; Dong, G.; Zou, W.; Chen, Z. Association between BDNF G196A (Val66Met)
polymorphism and cognitive impairment in patients with Parkinson’s disease: A meta-analysis. Braz. J. Med.
Biol. Res. 2019, 52, e8443. [CrossRef]
130. Franzmeier, N.; Ren, J.; Damm, A.; Monté-Rubio, G.; Boada, M.; Ruiz, A.; Ramirez, A.; Jessen, F.; Düzel, E.;
Rodríguez Gómez, O.; et al. The BDNF. Mol. Psychiatry 2019. [CrossRef]
131. Yin, Y.; Su, X.; Pan, L.; Li, C. BDNF Val66Met polymorphism and cognitive impairment in Parkinson’s
disease-a meta-analysis. Neurol. Sci. 2019, 40, 1901–1907. [CrossRef] [PubMed]
132. Dalby, R.B.; Elfving, B.; Poulsen, P.H.; Foldager, L.; Frandsen, J.; Videbech, P.; Rosenberg, R. Plasma
brain-derived neurotrophic factor and prefrontal white matter integrity in late-onset depression and normal
aging. Acta Psychiatr. Scand. 2013, 128, 387–396. [CrossRef] [PubMed]
133. Choi, S.; Han, K.M.; Won, E.; Yoon, B.J.; Lee, M.S.; Ham, B.J. Association of brain-derived neurotrophic factor
DNA methylation and reduced white matter integrity in the anterior corona radiata in major depression.
J. Affect. Disord. 2015, 172, 74–80. [CrossRef]
134. Youssef, M.M.; Underwood, M.D.; Huang, Y.Y.; Hsiung, S.C.; Liu, Y.; Simpson, N.R.; Bakalian, M.J.;
Rosoklija, G.B.; Dwork, A.J.; Arango, V.; et al. Association of BDNF Val66Met Polymorphism and Brain
BDNF Levels with Major Depression and Suicide. Int. J. Neuropsychopharmacol. 2018, 21, 528–538. [CrossRef]
135. Caldieraro, M.A.; McKee, M.; Leistner-Segal, S.; Vares, E.A.; Kubaski, F.; Spanemberg, L.;
Brusius-Facchin, A.C.; Fleck, M.P.; Mischoulon, D. Val66Met polymorphism association with serum BDNF
and inflammatory biomarkers in major depression. World J. Biol. Psychiatry 2018, 19, 402–409. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 7777 23 of 29

136. Rong, C.; Park, C.; Rosenblat, J.D.; Subramaniapillai, M.; Zuckerman, H.; Fus, D.; Lee, Y.L.; Pan, Z.; Brietzke, E.;
Mansur, R.B.; et al. Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder
and Bipolar Disorder. Int. J. Environ. Res. Public Health 2018, 15, 771. [CrossRef]
137. Mandolini, G.M.; Lazzaretti, M.; Pigoni, A.; Delvecchio, G.; Soares, J.C.; Brambilla, P. The impact of BDNF
Val66Met polymorphism on cognition in Bipolar Disorder: A review: Special Section on ”Translational and
Neuroscience Studies in Affective Disorders”Section Editor, Maria Nobile MD, PhD. This Section of JAD
focuses on the relevance of translational and neuroscience studies in providing a better understanding of the
neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical
neuroscience with particular regards to specific innovative topics in mood and anxiety disorders. J. Affect.
Disord. 2019, 243, 552–558. [CrossRef]
138. Chen, N.C.; Chuang, Y.C.; Huang, C.W.; Lui, C.C.; Lee, C.C.; Hsu, S.W.; Lin, P.H.; Lu, Y.T.; Chang, Y.T.;
Hsu, C.W.; et al. Interictal serum brain-derived neurotrophic factor level reflects white matter integrity,
epilepsy severity, and cognitive dysfunction in chronic temporal lobe epilepsy. Epilepsy Behav. 2016, 59,
147–154. [CrossRef] [PubMed]
139. Sidhu, M.K.; Thompson, P.J.; Wandschneider, B.; Foulkes, A.; de Tisi, J.; Stretton, J.; Perona, M.; Thom, M.;
Bonelli, S.B.; Burdett, J.; et al. The impact of brain-derived neurotrophic factor Val66Met polymorphism on
cognition and functional brain networks in patients with intractable partial epilepsy. CNS Neurosci. Ther.
2019, 25, 223–232. [CrossRef] [PubMed]
140. Doherty, C.; Hogue, O.; Floden, D.P.; Altemus, J.B.; Najm, I.M.; Eng, C.; Busch, R.M. BDNF and COMT, but
not APOE, alleles are associated with psychiatric symptoms in refractory epilepsy. Epilepsy Behav. 2019,
94, 131–136. [CrossRef]
141. Kheirollahi, M.; Kazemi, E.; Ashouri, S. Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism
and Risk of Schizophrenia: A Meta-analysis of Case-Control Studies. Cell. Mol. Neurobiol. 2016, 36, 1–10.
[CrossRef] [PubMed]
142. Xia, H.; Zhang, G.; Du, X.; Zhang, Y.; Yin, G.; Dai, J.; He, M.X.; Soares, J.C.; Li, X.; Zhang, X.Y. Suicide
attempt, clinical correlates, and BDNF Val66Met polymorphism in chronic patients with schizophrenia.
Neuropsychology 2018, 32, 199–205. [CrossRef]
143. Huang, E.; Hettige, N.C.; Zai, G.; Tomasi, J.; Huang, J.; Zai, C.C.; Pivac, N.; Nikolac Perkovic, M.;
Tiwari, A.K.; Kennedy, J.L. BDNF Val66Met polymorphism and clinical response to antipsychotic treatment in
schizophrenia and schizoaffective disorder patients: A meta-analysis. Pharmacogenomics J. 2019, 19, 269–276.
[CrossRef] [PubMed]
144. Han, M.; Deng, C. BDNF as a pharmacogenetic target for antipsychotic treatment of schizophrenia. Neurosci.
Lett. 2020, 726, 133870. [CrossRef] [PubMed]
145. Brown, A.; Machan, J.T.; Hayes, L.; Zervas, M. Molecular organization and timing of Wnt1 expression define
cohorts of midbrain dopamine neuron progenitors in vivo. J. Comp. Neurol. 2011, 519, 2978–3000. [CrossRef]
146. Ramos-Cejudo, J.; Gutiérrez-Fernández, M.; Otero-Ortega, L.; Rodríguez-Frutos, B.; Fuentes, B.;
Vallejo-Cremades, M.T.; Hernanz, T.N.; Cerdán, S.; Díez-Tejedor, E. Brain-derived neurotrophic factor
administration mediated oligodendrocyte differentiation and myelin formation in subcortical ischemic stroke.
Stroke 2015, 46, 221–228. [CrossRef]
147. Balkaya, M.; Cho, S. Genetics of stroke recovery: BDNF val66met polymorphism in stroke recovery and its
interaction with aging. Neurobiol. Dis. 2019, 126, 36–46. [CrossRef]
148. Lohia, R.; Salari, R.; Brannigan, G. Sequence specificity despite intrinsic disorder: How a disease-associated
Val/Met polymorphism rearranges tertiary interactions in a long disordered protein. PLoS Comput. Biol. 2019,
15, e1007390. [CrossRef]
149. Rock, P.L.; Roiser, J.P.; Riedel, W.J.; Blackwell, A.D. Cognitive impairment in depression: A systematic review
and meta-analysis. Psychol. Med. 2014, 44, 2029–2040. [CrossRef]
150. Severino, V.; Farina, A.; Colucci-D’Amato, L.; Reccia, M.G.; Volpicelli, F.; Parente, A.; Chambery, A. Secretome
profiling of differentiated neural mes-c-myc A1 cell line endowed with stem cell properties. Biochim. Biophys.
Acta 2013, 1834, 2385–2395. [CrossRef]
151. Colucci-D’Amato, L.; Farina, A.; Vissers, J.P.; Chambery, A. Quantitative neuroproteomics: Classical and
novel tools for studying neural differentiation and function. Stem Cell Rev. Rep. 2011, 7, 77–93. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 7777 24 of 29

152. Di Lieto, A.; Leo, D.; Volpicelli, F.; di Porzio, U.; Colucci-D’Amato, L. FLUOXETINE modifies the expression
of serotonergic markers in a differentiation-dependent fashion in the mesencephalic neural cell line A1 mes
c-myc. Brain Res. 2007, 1143, 1–10. [CrossRef] [PubMed]
153. Nawa, Y.; Kaneko, H.; Oda, M.; Tsubonoya, M.; Hiroi, T.; Gentile, M.T.; Colucci-D’Amato, L.; Takahashi, R.;
Matsui, H. Functional characterization of the neuron-restrictive silencer element in the human tryptophan
hydroxylase 2 gene expression. J. Neurochem. 2017, 142, 827–840. [CrossRef] [PubMed]
154. Gentile, M.T.; Nawa, Y.; Lunardi, G.; Florio, T.; Matsui, H.; Colucci-D’Amato, L. Tryptophan hydroxylase 2
(TPH2) in a neuronal cell line: Modulation by cell differentiation and NRSF/rest activity. J. Neurochem. 2012,
123, 963–970. [CrossRef] [PubMed]
155. Duman, R.S.; Heninger, G.R.; Nestler, E.J. A molecular and cellular theory of depression. Arch. Gen. Psychiatry
1997, 54, 597–606. [CrossRef] [PubMed]
156. Colucci-D’Amato, L.; di Porzio, U. Neurogenesis in adult CNS: From denial to opportunities and challenges
for therapy. Bioessays 2008, 30, 135–145. [CrossRef] [PubMed]
157. Colucci-D’Amato, L.; Bonavita, V.; di Porzio, U. The end of the central dogma of neurobiology: Stem cells
and neurogenesis in adult CNS. Neurol. Sci. 2006, 27, 266–270. [CrossRef] [PubMed]
158. Cramer, S.C.; Sur, M.; Dobkin, B.H.; O’Brien, C.; Sanger, T.D.; Trojanowski, J.Q.; Rumsey, J.M.; Hicks, R.;
Cameron, J.; Chen, D.; et al. Harnessing neuroplasticity for clinical applications. Brain 2011, 134, 1591–1609.
[CrossRef]
159. Castrén, E. Neuronal network plasticity and recovery from depression. JAMA Psychiatry 2013, 70, 983–989.
[CrossRef]
160. Snapyan, M.; Lemasson, M.; Brill, M.S.; Blais, M.; Massouh, M.; Ninkovic, J.; Gravel, C.; Berthod, F.; Götz, M.;
Barker, P.A.; et al. Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via
brain-derived neurotrophic factor signaling. J. Neurosci. 2009, 29, 4172–4188. [CrossRef]
161. Bergami, M.; Rimondini, R.; Santi, S.; Blum, R.; Götz, M.; Canossa, M. Deletion of TrkB in adult progenitors
alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proc. Natl.
Acad. Sci. USA 2008, 105, 15570–15575. [CrossRef] [PubMed]
162. Chan, K.L.; Tong, K.Y.; Yip, S.P. Relationship of serum brain-derived neurotrophic factor (BDNF) and
health-related lifestyle in healthy human subjects. Neurosci. Lett. 2008, 447, 124–128. [CrossRef]
163. Zafra, F.; Lindholm, D.; Castrén, E.; Hartikka, J.; Thoenen, H. Regulation of brain-derived neurotrophic factor
and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. J. Neurosci.
1992, 12, 4793–4799. [CrossRef] [PubMed]
164. Castrén, E.; Antila, H. Neuronal plasticity and neurotrophic factors in drug responses. Mol. Psychiatry 2017,
22, 1085–1095. [CrossRef] [PubMed]
165. Castrén, E.; Zafra, F.; Thoenen, H.; Lindholm, D. Light regulates expression of brain-derived neurotrophic
factor mRNA in rat visual cortex. Proc. Natl. Acad. Sci. USA 1992, 89, 9444–9448. [CrossRef] [PubMed]
166. Gianfranceschi, L.; Siciliano, R.; Walls, J.; Morales, B.; Kirkwood, A.; Huang, Z.J.; Tonegawa, S.; Maffei, L.
Visual cortex is rescued from the effects of dark rearing by overexpression of BDNF. Proc. Natl. Acad. Sci.
USA 2003, 100, 12486–12491. [CrossRef]
167. Hensch, T.K.; Bilimoria, P.M. Re-opening Windows: Manipulating Critical Periods for Brain Development.
Cerebrum 2012, 2012, 11.
168. Hong, E.J.; McCord, A.E.; Greenberg, M.E. A biological function for the neuronal activity-dependent
component of Bdnf transcription in the development of cortical inhibition. Neuron 2008, 60, 610–624.
[CrossRef]
169. Volpicelli, F.; Speranza, L.; di Porzio, U.; Crispino, M.; Perrone-Capano, C. The serotonin receptor 7 and the
structural plasticity of brain circuits. Front. Behav. Neurosci. 2014, 8, 318. [CrossRef]
170. Cazorla, M.; Arrang, J.M.; Prémont, J. Pharmacological characterization of six trkB antibodies reveals a novel
class of functional agents for the study of the BDNF receptor. Br. J. Pharmacol. 2011, 162, 947–960. [CrossRef]
171. Park, S.W.; Nhu, l.H.; Cho, H.Y.; Seo, M.K.; Lee, C.H.; Ly, N.N.; Choi, C.M.; Lee, B.J.; Kim, G.M.; Seol, W.;
et al. p11 mediates the BDNF-protective effects in dendritic outgrowth and spine formation in B27-deprived
primary hippocampal cells. J. Affect. Disord. 2016, 196, 1–10. [CrossRef]
172. Katoh-Semba, R.; Asano, T.; Ueda, H.; Morishita, R.; Takeuchi, I.K.; Inaguma, Y.; Kato, K. Riluzole enhances
expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in
the rat hippocampus. FASEB J. 2002, 16, 1328–1330. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 7777 25 of 29

173. Cavanaugh, J.E.; Ham, J.; Hetman, M.; Poser, S.; Yan, C.; Xia, Z. Differential regulation of mitogen-activated
protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J. Neurosci.
2001, 21, 434–443. [CrossRef]
174. Lin, E.; Cavanaugh, J.E.; Leak, R.K.; Perez, R.G.; Zigmond, M.J. Rapid activation of ERK by
6-hydroxydopamine promotes survival of dopaminergic cells. J. Neurosci. Res. 2008, 86, 108–117. [CrossRef]
[PubMed]
175. Rauti, R.; Cellot, G.; D’Andrea, P.; Colliva, A.; Scaini, D.; Tongiorgi, E.; Ballerini, L. BDNF impact on synaptic
dynamics: Extra or intracellular long-term release differently regulates cultured hippocampal synapses.
Mol. Brain 2020, 13, 43. [CrossRef] [PubMed]
176. Ernfors, P.; Lee, K.F.; Jaenisch, R. Mice lacking brain-derived neurotrophic factor develop with sensory
deficits. Nature 1994, 368, 147–150. [CrossRef]
177. Gao, X.; Smith, G.M.; Chen, J. Impaired dendritic development and synaptic formation of postnatal-born
dentate gyrus granular neurons in the absence of brain-derived neurotrophic factor signaling. Exp. Neurol.
2009, 215, 178–190. [CrossRef]
178. Mariga, A.; Zavadil, J.; Ginsberg, S.D.; Chao, M.V. Withdrawal of BDNF from hippocampal cultures leads to
changes in genes involved in synaptic function. Dev. Neurobiol. 2015, 75, 173–192. [CrossRef]
179. Aarse, J.; Herlitze, S.; Manahan-Vaughan, D. The requirement of BDNF for hippocampal synaptic plasticity
is experience-dependent. Hippocampus 2016, 26, 739–751. [CrossRef]
180. Magariños, A.M.; Li, C.J.; Gal Toth, J.; Bath, K.G.; Jing, D.; Lee, F.S.; McEwen, B.S. Effect of brain-derived
neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus
2011, 21, 253–264. [CrossRef]
181. von Bohlen Und Halbach, O.; von Bohlen Und Halbach, V. BDNF effects on dendritic spine morphology and
hippocampal function. Cell Tissue Res. 2018, 373, 729–741. [CrossRef]
182. von Bohlen und Halbach, O.; Minichiello, L.; Unsicker, K. TrkB but not trkC receptors are necessary for
postnatal maintenance of hippocampal spines. Neurobiol. Aging 2008, 29, 1247–1255. [CrossRef]
183. Dokter, M.; Busch, R.; Poser, R.; Vogt, M.A.; von Bohlen Und Halbach, V.; Gass, P.; Unsicker, K.; von Bohlen
Und Halbach, O. Implications of p75NTR for dentate gyrus morphology and hippocampus-related behavior
revisited. Brain Struct. Funct. 2015, 220, 1449–1462. [CrossRef]
184. Lin, P.Y.; Kavalali, E.T.; Monteggia, L.M. Genetic Dissection of Presynaptic and Postsynaptic BDNF-TrkB
Signaling in Synaptic Efficacy of CA3-CA1 Synapses. Cell Rep. 2018, 24, 1550–1561. [CrossRef]
185. Eyman, M.; Cefaliello, C.; Mandile, P.; Piscopo, S.; Crispino, M.; Giuditta, A. Training old rats selectively
modulates synaptosomal protein synthesis. J. Neurosci. Res. 2013, 91, 20–29. [CrossRef]
186. Nikoletopoulou, V.; Sidiropoulou, K.; Kallergi, E.; Dalezios, Y.; Tavernarakis, N. Modulation of Autophagy
by BDNF Underlies Synaptic Plasticity. Cell Metab. 2017, 26, 230–242. [CrossRef]
187. Fujimura, H.; Altar, C.A.; Chen, R.; Nakamura, T.; Nakahashi, T.; Kambayashi, J.; Sun, B.; Tandon, N.N.
Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb.
Haemost. 2002, 87, 728–734. [CrossRef]
188. Klein, A.B.; Williamson, R.; Santini, M.A.; Clemmensen, C.; Ettrup, A.; Rios, M.; Knudsen, G.M.; Aznar, S.
Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int. J. Neuropsychopharmacol.
2011, 14, 347–353. [CrossRef]
189. Mondal, A.C.; Fatima, M. Direct and indirect evidences of BDNF and NGF as key modulators in depression:
Role of antidepressants treatment. Int. J. Neurosci. 2019, 129, 283–296. [CrossRef]
190. Molendijk, M.L.; Spinhoven, P.; Polak, M.; Bus, B.A.; Penninx, B.W.; Elzinga, B.M. Serum BDNF concentrations
as peripheral manifestations of depression: Evidence from a systematic review and meta-analyses on 179
associations (N=9484). Mol. Psychiatry 2014, 19, 791–800. [CrossRef]
191. Polyakova, M.; Stuke, K.; Schuemberg, K.; Mueller, K.; Schoenknecht, P.; Schroeter, M.L. BDNF as a biomarker
for successful treatment of mood disorders: A systematic & quantitative meta-analysis. J. Affect. Disord. 2015,
174, 432–440. [CrossRef] [PubMed]
192. Kishi, T.; Yoshimura, R.; Ikuta, T.; Iwata, N. Brain-Derived Neurotrophic Factor and Major Depressive
Disorder: Evidence from Meta-Analyses. Front. Psychiatry 2017, 8, 308. [CrossRef] [PubMed]
193. Serra-Millàs, M. Are the changes in the peripheral brain-derived neurotrophic factor levels due to platelet
activation? World J. Psychiatry 2016, 6, 84–101. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2020, 21, 7777 26 of 29

194. Allen, A.P.; Naughton, M.; Dowling, J.; Walsh, A.; Ismail, F.; Shorten, G.; Scott, L.; McLoughlin, D.M.;
Cryan, J.F.; Dinan, T.G.; et al. Serum BDNF as a peripheral biomarker of treatment-resistant depression and
the rapid antidepressant response: A comparison of ketamine and ECT. J. Affect. Disord. 2015, 186, 306–311.
[CrossRef]
195. Lee, B.H.; Kim, Y.K. Reduced platelet BDNF level in patients with major depression. Prog. Neuropsychopharmacol.
Biol. Psychiatry 2009, 33, 849–853. [CrossRef]
196. Pandey, G.N.; Dwivedi, Y.; Rizavi, H.S.; Ren, X.; Zhang, H.; Pavuluri, M.N. Brain-derived neurotrophic factor
gene and protein expression in pediatric and adult depressed subjects. Prog. Neuropsychopharmacol. Biol.
Psychiatry 2010, 34, 645–651. [CrossRef]
197. Serra-Millàs, M.; López-Vílchez, I.; Navarro, V.; Galán, A.M.; Escolar, G.; Penadés, R.; Catalán, R.; Fañanás, L.;
Arias, B.; Gastó, C. Changes in plasma and platelet BDNF levels induced by S-citalopram in major depression.
Psychopharmacology 2011, 216, 1–8. [CrossRef]
198. Dwivedi, Y. The Neurobiological Basis of Suicide; CRC Press: Boca Raton, FL, USA, 2012.
199. Pandey, G.N.; Ren, X.; Rizavi, H.S.; Conley, R.R.; Roberts, R.C.; Dwivedi, Y. Brain-derived neurotrophic
factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims.
Int. J. Neuropsychopharmacol. 2008, 11, 1047–1061. [CrossRef]
200. Hosang, G.M.; Shiles, C.; Tansey, K.E.; McGuffin, P.; Uher, R. Interaction between stress and the BDNF
Val66Met polymorphism in depression: A systematic review and meta-analysis. BMC Med. 2014, 12, 7.
[CrossRef]
201. Li, M.; Du, W.; Shao, F.; Wang, W. Cognitive dysfunction and epigenetic alterations of the BDNF gene are
induced by social isolation during early adolescence. Behav. Brain Res. 2016, 313, 177–183. [CrossRef]
202. Yan, T.; Wang, L.; Kuang, W.; Xu, J.; Li, S.; Chen, J.; Yang, Y. Brain-derived neurotrophic factor Val66Met
polymorphism association with antidepressant efficacy: A systematic review and meta-analysis. Asia Pac.
Psychiatry 2014, 6, 241–251. [CrossRef]
203. Castrén, E.; Rantamäki, T. The role of BDNF and its receptors in depression and antidepressant drug action:
Reactivation of developmental plasticity. Dev. Neurobiol. 2010, 70, 289–297. [CrossRef] [PubMed]
204. Crispino, M.; Volpicelli, F.; Perrone-Capano, C. Role of the Serotonin Receptor 7 in Brain Plasticity: From
Development to Disease. Int. J. Mol. Sci. 2020, 21, 505. [CrossRef] [PubMed]
205. Alenina, N.; Klempin, F. The role of serotonin in adult hippocampal neurogenesis. Behav. Brain Res. 2015,
277, 49–57. [CrossRef] [PubMed]
206. Malberg, J.E.; Eisch, A.J.; Nestler, E.J.; Duman, R.S. Chronic antidepressant treatment increases neurogenesis
in adult rat hippocampus. J. Neurosci. 2000, 20, 9104–9110. [CrossRef] [PubMed]
207. Santarelli, L.; Saxe, M.; Gross, C.; Surget, A.; Battaglia, F.; Dulawa, S.; Weisstaub, N.; Lee, J.; Duman, R.;
Arancio, O.; et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.
Science 2003, 301, 805–809. [CrossRef]
208. Rantamäki, T.; Castrén, E. Targeting TrkB neurotrophin receptor to treat depression. Expert Opin. Ther. Targets
2008, 12, 705–715. [CrossRef] [PubMed]
209. Speranza, L.; Labus, J.; Volpicelli, F.; Guseva, D.; Lacivita, E.; Leopoldo, M.; Bellenchi, G.C.; di Porzio, U.;
Bijata, M.; Perrone-Capano, C.; et al. Serotonin 5-HT7 receptor increases the density of dendritic spines and
facilitates synaptogenesis in forebrain neurons. J. Neurochem. 2017, 141, 647–661. [CrossRef]
210. Speranza, L.; Giuliano, T.; Volpicelli, F.; De Stefano, M.E.; Lombardi, L.; Chambery, A.; Lacivita, E.;
Leopoldo, M.; Bellenchi, G.C.; di Porzio, U.; et al. Activation of 5-HT7 receptor stimulates neurite elongation
through mTOR, Cdc42 and actin filaments dynamics. Front. Behav. Neurosci. 2015, 9, 62. [CrossRef]
211. Speranza, L.; Chambery, A.; Di Domenico, M.; Crispino, M.; Severino, V.; Volpicelli, F.; Leopoldo, M.;
Bellenchi, G.C.; di Porzio, U.; Perrone-Capano, C. The serotonin receptor 7 promotes neurite outgrowth via
ERK and Cdk5 signaling pathways. Neuropharmacology 2013, 67, 155–167. [CrossRef]
212. Popova, N.K.; Naumenko, V.S. Neuronal and behavioral plasticity: The role of serotonin and BDNF systems
tandem. Expert Opin. Ther. Targets 2019, 23, 227–239. [CrossRef] [PubMed]
213. Castrén, E. Neurotrophins and psychiatric disorders. Handb. Exp. Pharmacol. 2014, 220, 461–479. [CrossRef]
[PubMed]
214. Castrén, E.; Kojima, M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments.
Neurobiol. Dis. 2017, 97, 119–126. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2020, 21, 7777 27 of 29

215. Castrén, E.; Rantamäki, T. Role of brain-derived neurotrophic factor in the aetiology of depression:
Implications for pharmacological treatment. CNS Drugs 2010, 24, 1–7. [CrossRef]
216. Lepack, A.E.; Fuchikami, M.; Dwyer, J.M.; Banasr, M.; Duman, R.S. BDNF release is required for the behavioral
actions of ketamine. Int. J. Neuropsychopharmacol. 2014, 18. [CrossRef]
217. Abdallah, C.G.; Sanacora, G.; Duman, R.S.; Krystal, J.H. Ketamine and rapid-acting antidepressants:
A window into a new neurobiology for mood disorder therapeutics. Annu. Rev. Med. 2015, 66, 509–523.
[CrossRef] [PubMed]
218. Monteggia, L.M.; Zarate, C. Antidepressant actions of ketamine: From molecular mechanisms to clinical
practice. Curr. Opin. Neurobiol. 2015, 30, 139–143. [CrossRef] [PubMed]
219. Björkholm, C.; Monteggia, L.M. BDNF-a key transducer of antidepressant effects. Neuropharmacology 2016,
102, 72–79. [CrossRef] [PubMed]
220. Hoshaw, B.A.; Malberg, J.E.; Lucki, I. Central administration of IGF-I and BDNF leads to long-lasting
antidepressant-like effects. Brain Res. 2005, 1037, 204–208. [CrossRef]
221. Eisch, A.J.; Bolaños, C.A.; de Wit, J.; Simonak, R.D.; Pudiak, C.M.; Barrot, M.; Verhaagen, J.; Nestler, E.J.
Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: A role in depression.
Biol. Psychiatry 2003, 54, 994–1005. [CrossRef]
222. Monteggia, L.M.; Luikart, B.; Barrot, M.; Theobold, D.; Malkovska, I.; Nef, S.; Parada, L.F.; Nestler, E.J.
Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related
behaviors. Biol. Psychiatry 2007, 61, 187–197. [CrossRef] [PubMed]
223. Monteggia, L.M.; Barrot, M.; Powell, C.M.; Berton, O.; Galanis, V.; Gemelli, T.; Meuth, S.; Nagy, A.;
Greene, R.W.; Nestler, E.J. Essential role of brain-derived neurotrophic factor in adult hippocampal function.
Proc. Natl. Acad. Sci. USA 2004, 101, 10827–10832. [CrossRef] [PubMed]
224. Saarelainen, T.; Hendolin, P.; Lucas, G.; Koponen, E.; Sairanen, M.; MacDonald, E.; Agerman, K.; Haapasalo, A.;
Nawa, H.; Aloyz, R.; et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs
and is required for antidepressant-induced behavioral effects. J. Neurosci. 2003, 23, 349–357. [CrossRef]
[PubMed]
225. Li, Y.; Luikart, B.W.; Birnbaum, S.; Chen, J.; Kwon, C.H.; Kernie, S.G.; Bassel-Duby, R.; Parada, L.F. TrkB
regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 2008,
59, 399–412. [CrossRef]
226. Liu, R.J.; Lee, F.S.; Li, X.Y.; Bambico, F.; Duman, R.S.; Aghajanian, G.K. Brain-derived neurotrophic factor
Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol. Psychiatry
2012, 71, 996–1005. [CrossRef]
227. Kato, T.; Fogaça, M.V.; Deyama, S.; Li, X.Y.; Fukumoto, K.; Duman, R.S. BDNF release and signaling are
required for the antidepressant actions of GLYX-13. Mol. Psychiatry 2018, 23, 2007–2017. [CrossRef]
228. Herring, M.P.; Puetz, T.W.; O’Connor, P.J.; Dishman, R.K. Effect of exercise training on depressive symptoms
among patients with a chronic illness: A systematic review and meta-analysis of randomized controlled
trials. Arch. Intern. Med. 2012, 172, 101–111. [CrossRef]
229. Ota, K.T.; Duman, R.S. Environmental and pharmacological modulations of cellular plasticity: Role in the
pathophysiology and treatment of depression. Neurobiol. Dis. 2013, 57, 28–37. [CrossRef]
230. Schuch, F.B.; Vancampfort, D.; Richards, J.; Rosenbaum, S.; Ward, P.B.; Stubbs, B. Exercise as a treatment for
depression: A meta-analysis adjusting for publication bias. J. Psychiatr. Res. 2016, 77, 42–51. [CrossRef]
231. Rasmussen, P.; Brassard, P.; Adser, H.; Pedersen, M.V.; Leick, L.; Hart, E.; Secher, N.H.; Pedersen, B.K.;
Pilegaard, H. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise.
Exp. Physiol. 2009, 94, 1062–1069. [CrossRef]
232. Seifert, T.; Brassard, P.; Wissenberg, M.; Rasmussen, P.; Nordby, P.; Stallknecht, B.; Adser, H.; Jakobsen, A.H.;
Pilegaard, H.; Nielsen, H.B.; et al. Endurance training enhances BDNF release from the human brain. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 2010, 298, R372–R377. [CrossRef] [PubMed]
233. Xu, L.; Zheng, Y.L.; Yin, X.; Xu, S.J.; Tian, D.; Zhang, C.Y.; Wang, S.; Ma, J.Z. Excessive Treadmill Training
Enhances Brain-Specific MicroRNA-34a in the Mouse Hippocampus. Front. Mol. Neurosci. 2020, 13, 7.
[CrossRef] [PubMed]
234. de Assis, G.G.; de Almondes, K.M. Exercise-dependent BDNF as a Modulatory Factor for the Executive
Processing of Individuals in Course of Cognitive Decline. A Systematic Review. Front. Psychol. 2017, 8, 584.
[CrossRef] [PubMed]
Int. J. Mol. Sci. 2020, 21, 7777 28 of 29

235. Pajonk, F.G.; Wobrock, T.; Gruber, O.; Scherk, H.; Berner, D.; Kaizl, I.; Kierer, A.; Müller, S.; Oest, M.; Meyer, T.;
et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch. Gen. Psychiatry 2010, 67, 133–143.
[CrossRef] [PubMed]
236. Moon, H.Y.; Becke, A.; Berron, D.; Becker, B.; Sah, N.; Benoni, G.; Janke, E.; Lubejko, S.T.; Greig, N.H.;
Mattison, J.A.; et al. Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function.
Cell Metab. 2016, 24, 332–340. [CrossRef] [PubMed]
237. Boström, P.; Wu, J.; Jedrychowski, M.P.; Korde, A.; Ye, L.; Lo, J.C.; Rasbach, K.A.; Boström, E.A.; Choi, J.H.;
Long, J.Z.; et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and
thermogenesis. Nature 2012, 481, 463–468. [CrossRef]
238. Wrann, C.D.; White, J.P.; Salogiannnis, J.; Laznik-Bogoslavski, D.; Wu, J.; Ma, D.; Lin, J.D.; Greenberg, M.E.;
Spiegelman, B.M. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab.
2013, 18, 649–659. [CrossRef]
239. Müller, P.; Duderstadt, Y.; Lessmann, V.; Müller, N.G. Lactate and BDNF: Key Mediators of Exercise Induced
Neuroplasticity? J. Clin. Med. 2020, 9, 1136. [CrossRef]
240. Piotrowicz, Z.; Chalimoniuk, M.; Płoszczyca, K.; Czuba, M.; Langfort, J. Exercise-Induced Elevated BDNF
Level Does Not Prevent Cognitive Impairment Due to Acute Exposure to Moderate Hypoxia in Well-Trained
Athletes. Int. J. Mol. Sci. 2020, 21, 5569. [CrossRef]
241. Miranda, M.; Morici, J.F.; Zanoni, M.B.; Bekinschtein, P. Brain-Derived Neurotrophic Factor: A Key Molecule
for Memory in the Healthy and the Pathological Brain. Front. Cell Neurosci. 2019, 13, 363. [CrossRef]
242. Hock, C.; Heese, K.; Hulette, C.; Rosenberg, C.; Otten, U. Region-specific neurotrophin imbalances in
Alzheimer disease: Decreased levels of brain-derived neurotrophic factor and increased levels of nerve
growth factor in hippocampus and cortical areas. Arch. Neurol. 2000, 57, 846–851. [CrossRef]
243. Zuccato, C.; Marullo, M.; Conforti, P.; MacDonald, M.E.; Tartari, M.; Cattaneo, E. Systematic assessment
of BDNF and its receptor levels in human cortices affected by Huntington0 s disease. Brain Pathol. 2008,
18, 225–238. [CrossRef] [PubMed]
244. Narisawa-Saito, M.; Wakabayashi, K.; Tsuji, S.; Takahashi, H.; Nawa, H. Regional specificity of alterations in
NGF, BDNF and NT-3 levels in Alzheimer0 s disease. Neuroreport 1996, 7, 2925–2928. [CrossRef]
245. Hoxha, E.; Lippiello, P.; Zurlo, F.; Balbo, I.; Santamaria, R.; Tempia, F.; Miniaci, M.C. The Emerging Role
of Altered Cerebellar Synaptic Processing in Alzheimer’s Disease. Front. Aging Neurosci. 2018, 10, 396.
[CrossRef] [PubMed]
246. Peng, S.; Wuu, J.; Mufson, E.J.; Fahnestock, M. Precursor form of brain-derived neurotrophic factor and
mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease.
J. Neurochem. 2005, 93, 1412–1421. [CrossRef] [PubMed]
247. Choi, S.H.; Bylykbashi, E.; Chatila, Z.K.; Lee, S.W.; Pulli, B.; Clemenson, G.D.; Kim, E.; Rompala, A.;
Oram, M.K.; Asselin, C.; et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition
in an Alzheimer’s mouse model. Science 2018, 361. [CrossRef] [PubMed]
248. Sleiman, S.F.; Henry, J.; Al-Haddad, R.; El Hayek, L.; Abou Haidar, E.; Stringer, T.; Ulja, D.;
Karuppagounder, S.S.; Holson, E.B.; Ratan, R.R.; et al. Exercise promotes the expression of brain derived
neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elife 2016, 5. [CrossRef]
[PubMed]
249. Colucci-D’Amato, L.; Perrone-Capano, C.; di Porzio, U. Chronic activation of ERK and neurodegenerative
diseases. Bioessays 2003, 25, 1085–1095. [CrossRef] [PubMed]
250. Kirouac, L.; Rajic, A.J.; Cribbs, D.H.; Padmanabhan, J. Activation of Ras-ERK Signaling and GSK-3 by
Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer0 s Disease. eNeuro
2017, 4. [CrossRef]
251. Nizzari, M.; Barbieri, F.; Gentile, M.T.; Passarella, D.; Caorsi, C.; Diaspro, A.; Taglialatela, M.; Pagano, A.;
Colucci-D’Amato, L.; Florio, T.; et al. Amyloid-β protein precursor regulates phosphorylation and cellular
compartmentalization of microtubule associated protein tau. J. Alzheimers Dis. 2012, 29, 211–227. [CrossRef]
252. Bartolotti, N.; Segura, L.; Lazarov, O. Diminished CRE-Induced Plasticity is Linked to Memory Deficits in
Familial Alzheimer’s Disease Mice. J. Alzheimers Dis. 2016, 50, 477–489. [CrossRef] [PubMed]
253. Rosa, E.; Fahnestock, M. CREB expression mediates amyloid β-induced basal BDNF downregulation.
Neurobiol. Aging 2015, 36, 2406–2413. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2020, 21, 7777 29 of 29

254. Thiele, C.J.; Li, Z.; McKee, A.E. On Trk–the TrkB signal transduction pathway is an increasingly important
target in cancer biology. Clin. Cancer Res. 2009, 15, 5962–5967. [CrossRef] [PubMed]
255. Xiong, J.; Zhou, L.I.; Lim, Y.; Yang, M.; Zhu, Y.H.; Li, Z.W.; Fu, D.L.; Zhou, X.F. Mature brain-derived
neurotrophic factor and its receptor TrkB are upregulated in human glioma tissues. Oncol. Lett. 2015, 10,
223–227. [CrossRef] [PubMed]
256. Colucci-D’Amato, G.L.; D’Alessio, A.; Califano, D.; Cali, G.; Rizzo, C.; Nitsch, L.; Santelli, G.; de Franciscis, V.
Abrogation of nerve growth factor-induced terminal differentiation by ret oncogene involves perturbation of
nuclear translocation of ERK. J. Biol. Chem. 2000, 275, 19306–19314. [CrossRef]
257. Radin, D.P.; Patel, P. BDNF: An Oncogene or Tumor Suppressor? Anticancer. Res. 2017, 37, 3983–3990.
[CrossRef]
258. Wang, X.; Prager, B.C.; Wu, Q.; Kim, L.J.Y.; Gimple, R.C.; Shi, Y.; Yang, K.; Morton, A.R.; Zhou, W.; Zhu, Z.; et al.
Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant
Progression. Cell Stem Cell 2018, 22, 514–528. [CrossRef]
259. Garofalo, S.; D’Alessandro, G.; Chece, G.; Brau, F.; Maggi, L.; Rosa, A.; Porzia, A.; Mainiero, F.; Esposito, V.;
Lauro, C.; et al. Enriched environment reduces glioma growth through immune and non-immune mechanisms
in mice. Nat. Commun. 2015, 6, 6623. [CrossRef]
260. Garofalo, S.; Porzia, A.; Mainiero, F.; Di Angelantonio, S.; Cortese, B.; Basilico, B.; Pagani, F.; Cignitti, G.;
Chece, G.; Maggio, R.; et al. Environmental stimuli shape microglial plasticity in glioma. Elife 2017, 6.
[CrossRef]
261. Colucci-D’Amato, L.; Cimaglia, G. As a potential source of neuroactive compounds to promote and restore
neural functions. J. Tradit. Complement. Med. 2020, 10, 309–314. [CrossRef]
262. Gentile, M.T.; Ciniglia, C.; Reccia, M.G.; Volpicelli, F.; Gatti, M.; Thellung, S.; Florio, T.; Melone, M.A.;
Colucci-D’Amato, L. Ruta graveolens L. induces death of glioblastoma cells and neural progenitors, but not
of neurons, via ERK 1/2 and AKT activation. PLoS ONE 2015, 10, e0118864. [CrossRef] [PubMed]

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