GABAergic Neurotransmission

Recent advances in the study of alcoholism have thrown
light on the involvement of various neurotransmitters in the
phenomenon of alcohol addiction. Various neurotransmitters
have been implicated in alcohol addiction due to their
imbalance in the brain, which could be either due to their
excess activity or inhibition. This review paper aims to
consolidate and to summarize some of the recent papers
which have been published in this regard. The review
paper will give an overview of the neurobiology of alcohol
addiction, followed by detailed reviews of some of the recent
papers published in the context of the genetics of alcohol
addiction. Furthermore, the author hopes that the present
text will be found useful to novices and experts alike in the
field of neurotransmitters in alcoholism.

Neurochemistry and drug addiction. Neurocognitive approach. Cognitive Neuroscience. Research for the Postgraduate Program in Cognitive Sciences of the University of Costa Rica. This research establishes a theoretical basis for the biochemical and neurophysiological bases of behavior and mental phenomena, as well as analyzing the neuropathologies derived from the consumption of toxic substances. Plausible explanations are given for the relationships between toxic and addictive and addictive behaviors, and their neurophysiological and genetic bases. // Neuroquímica y toxicodependencia. Enfoque de neurocognoscitivo.  Neurociencias Cognoscitivas. Investigación para el Programa de Postgrado en Ciencias Cognoscitivas de la Universidad de Costa Rica.  Esta investigación, establece una fundamenta teórica de las bases bioquímicas y neurofisiológicas de la conducta y de los fenómenos mentales, así como analiza las neuropatologías derivadas del consumo de tóxicos. Se plantean explicaciones plausibles de las relaciones entre tóxicos y conductas dependientes y adictivas, y sus bases neurofisiológicas y genéticas. // Rodolfo J. Rodríguez-Rodríguez. E-Mail: rodolfojrr@gmx.com

Background: Śilājatu (Shilajit; SJ) is claimed in traditional Indian medical practice to be useful in the treatment of nervous disorders, epilepsy and as antistress.
Aim: To investigate whether SJ possesses antiepileptic and antipsychotic activities in rodents.
Materials and Methods: Isonicotinyl hydrazine (INH), pentylenetetrazole (PTZ), apomorphine, phenytoin, diazepam, haloperidol and other chemicals of analytical grade were procured from standard companies. The antiepileptic activity of SJ was assessed using maximal electro shock (MES)-induced seizures in rats, INH and PTZ-induced seizures in mice. The antipsychotic effect of SJ was evaluated using apomorphine-induced climbing and stereotyped behaviours respectively, in mice and rats.
Settings and Designs: SJ (25 and 50 mg/kg, p.o.) was given orally once daily for 15 days in all the rodent models. On the test day, SJ was administered 1 h prior to electric shock or chemical inducers (INH/PTZ/apomorphine) in experimental animals; the animals were then observed for different phases of seizures and psychotic behaviours. In addition, gamma-aminobutyric acid (GABA) content in the brain of rats and mice was estimated in seizure models.
Statistical Analysis: The data were expressed as mean ± standard error of mean. Statistical comparisons were performed by one-way ANOVA followed by Tukey's post-test using Graph Pad Prism version 5.0, USA. A P < 0.05 was considered significant.
Results and Conclusions: SJ pretreatment significantly inhibited the seizures induced by MES, INH and PTZ in a dose dependent manner. Further, SJ augmented brain GABA levels to normal, decreased by INH and PTZ in mice brain. SJ pretreatment also significantly inhibited the climbing and stereotyped behaviours induced by apomorphine. The present data seems to confirm the antiepileptic activity of SJ which may be because of enhancing the GABAergic system. The antipsychotic activity observed may be due to anti-dopaminergic and/or GABA-mimetic actions.

Interactions between presynaptic and postsynaptic cellular adhesion molecules (CAMs) drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of CAM RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic adhesion proteins is associated with disrupted glutamatergic and gamma-aminobutyric acid signaling, resulting in loss of activity-dependent neuronal plasticity, and risk for developmental disorders, including autism. While the majority of genetic mutations currently linked to autism are rare variants that change the protein-coding sequence of synaptic candidate genes, regulatory polymorphisms affecting constitutive and alternative splicing have emerged as risk factors in numerous other diseases, accounting for an estimated 40–60% of general disease risk. Here, we review the relationship between aberrant RNA splicing of synapse-related genes and autism spectrum disorders.

The diagnostic nomenclature of bipolar affective dysfunction is distinguished from unipolar mood dysfunction by the presence of mania. The bipolar disorder criteria reflect the current psychiatric understanding of manic-depressive illness and affective psychosis described in the nineteenth

Biological membranes define the boundaries of cells and compartmentalize the chemical and physical processes required for life. Many biological processes are carried out by proteins embedded in or associated with such membranes. Determination of membrane protein (MP) structures at atomic or near-atomic resolution plays a vital role in elucidating their structural and functional impact in biology. This endeavor has determined 1198 unique MP structures as of early 2021. The value of these structures is expanded greatly by deposition of their three-dimensional (3D) coordinates into the Protein Data Bank (PDB) after the first atomic MP structure was elucidated in 1985. Since then, free access to MP structures facilitates broader and deeper understanding of MPs, which provides crucial new insights into their biological functions. Here we highlight the structural and functional biology of representative MPs and landmarks in the evolution of new technologies, with insights into key developments influenced by the PDB in magnifying their impact. As membranes were critical to the separation of chemistries essential to the origin of life, membrane proteins (MPs) are key players in some of the most important physiological processes in living organisms. Characterizing MPs structurally and functionally is still extremely challenging due to their frequent low abundance, and difficulties in purifying functional MPs intact from their native membrane, though it is going through an exciting revolution now due to several key factors. It took several decades to obtain the structural information that now allows pursuit of understanding MP function in health and disease, to manipulate them as drug targets, and to engineer them into new powerful tools to fuel discovery. We highlight some of the landmarks in this endeavor that drove or depended on the discovery of new technologies required specifically for structural studies of membrane, versus soluble proteins. Previously, handwritten letters delivered by post requested coordinate sets that were not always readily given. The vision of Hamilton, Myer, Koetzle, and the joint venture between the Cambridge Crystallographic Data Center in the United Kingdom and the Brookhaven National Laboratories at Stony Brook University led to the Protein Data Bank (PDB). Then for the first time, one could begin to ask questions with all the relevant structures at hand. In celebrating 50 years of the PDB, we focus on some of the ingeniously crafted inventions and discoveries that led the way for entire classes of MPs, and those new approaches that now promise structures of large and complex machines from their native cellular environments, in action. In the following Historical perspective, we provide a brief historical perspective of some MP insights (other than the crucial G-protein-coupled receptors (GPCRs) that are the subject of a dedicated review in this volume) and consider the value of the PDB in disseminating this information. Seemingly insurmountable difficulties were often overcome with invention of new technologies to reveal important structural features of classes of MPs that make the fabric of today's approaches. In How do membrane proteins accomplish key physiological functions?, we describe how the structures of several of the major MP classes were uncovered, which often required technological developments that are now woven into the fabric of structural biology. First, how are the α-helical, tail-anchored, and all β-sheet MP broad categories correctly targeted to and inserted into membranes and allowed to fold correctly? We progress to landmark discoveries involving the roles of MPs in physiology and some of the critical barriers that had to be overcome to realize these achievements. How do water channels conduct water at diffusion limited rates without allowing leakage of protons (H +) or hydronium ions (H 3 O +) or any other ions? How do potassium channels conduct K + ions, but ‡ These authors contributed equally.

Cases of recovery from vegetative and minimally conscious state after the administration of various pharmacological agents have been recently reported. These agents include CNS depressants (zolpidem, baclofen, lamotrigine) and CNS stimulants (tricyclic anti-depressants, selective serotonin reuptake inhibitors, dopaminergic agents, methylphenidate). The action of CNS depressants as awakening agents sounds paradoxical, as they are commonly prescribed to slow down brain activity in the management of anxiety, muscle tension, pain, insomnia and seizures. How these drugs may improve the level of consciousness in some brain-injured patients is the subject of intense debate. Here we hypothesize that CNS depressants may promote consciousness recovery by reversing a condition of GABA impairment in the injured brain, restoring the normal ratio between synaptic excitation and inhibition, which is the prerequisite for any transition from a resting state to goal-oriented activities (GABA impairment hypothesis). Alternative or complementary mechanisms underlying the improvement of consciousness may include the reversal of a neurodormant state within areas affected by diaschisis (diaschisis hypothesis) and the modulation of an informative overload to the cortex as a consequence of filter failure in the injured brain (informative overload hypothesis). A better understanding of how single agents act on neural networks, whose functioning is critical for recovery, may help to advance a tailored pharmacological approach in the treatment of severely brain injured patients.

Key points r The laserspritzer we developed activates axo-axonic synapses (AASs) with spatial resolutions of less than 40 μm. r AASs innervate the entire length of the axon initial segment (AIS), as opposed to forming a highly concentrated cartridge. r AAS-mediated synaptic potentials are inhibitory, with reversal potentials similar to those of basket synapses. r AAS inhibition impedes action potentials and epileptiform activity more robustly than peri-somatic inhibitions. r AAS activation alone is sufficient to inhibit action potential generation and epileptiform activities in vitro. Abstract GABAergic terminals of chandelier cells exclusively innervate the axon initial segment (AIS) of excitatory neurons. Although the anatomy of these synapses has been well-studied in several brain areas, relatively little is known about their physiological properties. Using vesicular γ-aminobutyric acid transporter–channelrhodopsin 2–enhanced yellow fluorescence protein (VGAT-ChR2-YFP)-expressing mice and a novel fibreoptic 'laserspritzer' approach that we developed, we investigated the physiological properties of axo-axonic synapses (AASs) in brain slices from the piriform cortex (PC) of mice. AASs were in close proximity to voltage-gated Na + (Na V) channels located at the AIS. AASs were selectively activated by a 5 μm laserspritzer placed in close proximity to the AIS. Under a minimal laser stimulation condition and using whole-cell somatic voltage-clamp recordings, the amplitudes and kinetics of IPSCs mediated by AASs were similar to those mediated by perisomatic inhibitions. Results were further validated with channelrhodopsin 2-assisted circuit mapping (CRACM) of the entire inhibitory inputs map. For the first time, we revealed that the laserspritzer-induced AAS-IPSCs persisted in the presence of TTX and TEA but not 4-AP. Next, using gramicidin-based perforated patch recordings, we found that the GABA reversal potential (E GABA) was −73.6 ± 1.2 mV when induced at the AIS and −72.8 ± 1.1 mV when induced at the perisomatic site. Our anatomical and physiological results lead to the novel conclusions that: (1) AASs innervate the entire length of the AIS, as opposed to forming a highly concentrated cartridge, (2) AAS inhibition suppresses action potentials and epileptiform activity more robustly than perisomatic inhibitions, and (3) AAS activation alone can be sufficient to inhibit action potential generation and epileptiform activities in vitro.

The primary somatosensory cortex (SI) is a critical part of the neural substrate underlying interindividual differences in pain sensitivity. Here, we investigated whether resting-state functional connectivity, gray matter density (GMD), and GABA and Glx (glutamate and glutamine) levels of the sensorimotor cortices were related to pain thresholds and whether such imaging measures could predict high and low pain sensitivity. Functional, structural, and spectroscopic magnetic resonance data were obtained from 48 healthy participants together with pain thresholds of the right index finger. Left and right sensorimotor networks (SMN) were extracted by means of independent component analysis, and GMD was measured within the combined SMN by means of voxel-based morphometry. Spectroscopic data were acquired from the bilateral sensorimotor cortices. Within the left SMN, functional connectivity to the right SI correlated positively with pain thresholds. In addition, GMD in the left SI and the GABA laterality index correlated positively with pain thresholds. A positive correlation was also found between the GABA laterality index and the left SMN connectivity to the right SI. Finally, the above mentioned functional connectivity and GMD measures could correctly predict high and low pain sensitivity in 83.7% of the study population. In summary, we showed that interindividual differences in pain sensitivity were related to the resting-state functional connectivity, interhemispheric GABA tone, and GMD of the sensorimotor cortices. Furthermore, high and low pain sensitivity could be predicted with high accuracy using imaging measures from the primary sensorimotor cortices.

Objectives: To investigate the alterations in GABA levels by rolipram in the model of depression.  Materials and Methods: The alteration of GABA content by rolipram as a phosphodiesterase enzyme type-4 inhibitor in the frontal cortex (FCx; as a brain region crucial for the control of emotion and cognition) obtained from male mice exposed to chronic mild stress (CMS)-induced anhedonia (the loss of pleasure or lack of sensitivity to pleasure stimuli) was recorded. Results: The results demonstrated the reversal of CMS-induced anhedonia after 3 weeks per os of rolipram in a dose of 0.1 mg/kg/day dissolved in distilled water. Furthermore, rolipram showed a significant reduction in duration of immobility in long-term behavioral changes recorded by the FST. Additionally, there was a significant increase in the GABA content of the FCx of rolipram-treated mice exposed to CMS-induced anhedonia. Conclusions: The present study suggested that GABA levels may be decreased in an animal model of depression and its reversal together with the behaviour improvement by rolipram could support the hypothesis that modification in GABAergic activity has a role in mood disorders. These effects may complement the antidepressant effect of rolipram that is originally mediated via inhibition of phosphodiesterase enzyme type-4 [PDE4] that increases cyclic adenosine monophosphate signalling the pharmacotherapy of depression. Key words: Chronic mild stress, depression, forced swimming test, γ-amino butyric acid, rolipram

Abnormalities of GABAergic interneurons are some of the most consistent findings from post-mortem studies of schizophrenia. However, linking these molecular deficits with in vivo observations in patients – a critical goal in order to evaluate interventions that would target GABAergic deficits – presents a challenge. Explanatory models have been developed based on animal work and the emerging experimental literature in schizophrenia patients. This literature includes: neuroimaging ligands to GABA receptors, magnetic resonance spectroscopy (MRS) of GABA concentration, transcranial magnetic stimulation of cortical inhibitory circuits and pharmacologic probes of GABA receptors to dynamically challenge the GABA system, usually in combination with neuroimaging studies. Pharmacologic challenges have elicited behavioral changes, and preliminary studies of therapeutic GABAergic interventions have been conducted. This article critically reviews the evidence for GABAergic dysfunction from each of these areas. These methods remain indirect measures of GABAergic function, and a broad array of dysfunction is linked with the putative GABAergic measures, including positive symptoms, cognition, emotion, motor processing and sensory processing, covering diverse brain areas. Measures of receptor binding have not shown replicable group differences in binding, and MRS assays of GABA concentration have yielded equivocal evidence of large-scale alteration in GABA concentration. Overall, the experimental base remains sparse, and much remains to be learned about the role of GABAergic interneurons in healthy brains. Challenges with pharmacologic and functional probes show promise, and may yet enable a better characterization of GABAergic deficits in schizophrenia.

The neurotransmitter molecule γ-aminobutyric acid (GABA) promotes sleep in mammals and flies, but the molecular details of this regulation have not been clear. Chen et al. provide new insight into this complex pathway, finding that GABA transaminase (GABAT), a mitochondrial enzyme that breaks down GABA, controls GABA amounts to affect sleep in Drosophila. Sleep is controlled by the protein sleepless (SSS), which is expressed in neurons of the fly brain. SURESH KUMAR.S GABA transaminase (GABAT), a mitochondrial enzyme that breaks down GABA, controls GABA amounts to affect sleep ,in a possibly calcium dependent pathway.Sleep is an essential process conserved from flies to humans. The importance of sleep is underscored by its tight homeostatic control. Biothermal influences are important in bioenergetic mitochondrial enzyme processes.Mitochondrial calcium migration correlates with such enzymatic processes in cellular energy centers.The thermal conditions would probably affect calcium signalling such that close homeostatic biothermalisation control might be required. There are cooling mechanisms associated

Vasoactive intestinal peptide (VIP) is an important modulator of hippocampal synaptic transmission that influences both GABAergic synaptic transmission and glutamatergic cell excitability through activation of VPAC 1 and VPAC 2 receptors. Presynaptic enhancement of GABA release contributes to VIP modulation of hippocampal synaptic transmission. EXPERIMENTAL APPROACH We investigated which VIP receptors and coupled transduction pathways were involved in VIP enhancement of K +-evoked [ 3 H]-GABA release from isolated nerve terminals of rat hippocampus. KEY RESULTS VIP enhancement of [ 3 H]-GABA release was potentiated in the presence of the VPAC 1 receptor antagonist PG 97-269 but converted into an inhibition in the presence of the VPAC 2 receptor antagonist PG 99-465, suggesting that activation of VPAC 1 receptors inhibits and activation of VPAC 2 receptors enhances, GABA release. A VPAC 1 receptor agonist inhibited exocytotic voltage-gated calcium channel (VGCC)-dependent [ 3 H]-GABA release through activation of protein G i/o , an effect also dependent on PKC activity. A VPAC 2 receptor agonist enhanced both exocytotic VGCC-dependent release through protein G s-dependent, PKA-dependent and PKC-dependent mechanisms and GABA transporter 1-mediated [ 3 H]-GABA release through a G s protein-dependent and PKC-dependent mechanism. CONCLUSIONS AND IMPLICATIONS Our results show that VPAC 1 and VPAC 2 VIP receptors have opposing actions on GABA release from hippocampal nerve terminals through activation of different transduction pathways. As VPAC 1 and VPAC 2 receptors are located in different layers of Ammon's horn, our results suggest that these VIP receptors underlie different modulation of synaptic transmission to pyramidal cell dendrites and cell bodies, with important consequences for their possible therapeutic application in the treatment of epilepsy.

Aims. The biological mechanisms of epilepsy allow pathophysiological patterns to be established which are
essential for the selection of new therapeutic targets. The identification of these mechanisms also provides us with knowledge
about the dynamics of neuronal arrangement, synaptogenesis, synaptic transmission and the receptors involved, and even the
development of the brain. Development. Recent advances in neurobiology regarding the GABAergic system point to it as
playing a leading role in the pathophysiology of epilepsy. We evaluate the different functional formats of the ionotropic (GABAA)
and metabotropic (GABAB) gamma-aminobutyric (GABA) receptors. Although the main function posited is inhibitory, owing to
the variability of their location, subunits and neuronal physiology/maturation they can even end up expressing excitatory
functions. We discuss the anomalies in the GABAergic system identified in animal models with epilepsy and in brain tissue
samples from patients submitted to surgery due to epilepsy. The mechanism inhibiting the activation of GABA receptors is
performed by hyperpolarisation achieved by entry of Cl– into the neuron –a process mediated by the cotransporter KCC2,
typically expressed in the neuron. Mutations in the KCC2 gene produce mice that are susceptible to seizures. In some animal
models it has been found that loop diuretics (furosemide) suppress seizures. Mutations in genes that code for ion channels have
been identified in numerous epileptic syndromes and this pushes epilepsy ever further inside the broad group of disorders known
as channelopathies. The origin could be polygenetic in many cases. Conclusions. The GABAergic system seems to situate itself
as the main system implicated in the pathophysiology of epilepsy, although conditions that have been considered to be
idiopathic up till now could have a polygenic nature.

Quetiapine is a novel antipsychotic drug. However, there is limited clinical evidence regarding prescribing patterns for quetiapine when used as maintenance treatment for bipolar disorder.  Thirty-six albino rats were divided into 3 equal groups: control normal group [1] without exposure to chronic restraint for 6 hours daily/21 days, group [2] received DMSO 5% (v:v), as a solvent of quetiapine, with exposure to chronic restraint for 6 hours daily/21 days and group [3] received quetiapine 10 mg/kg/day ip for 3 weeks during exposure to chronic restraint for 6 hours daily/21 days.  Intraperitoneal (ip) administration of quetiapine at a dose of 10 mg/kg/day for 3 weeks significantly (p<0.05) reduces the duration of immobility recorded by the forced swimming test (FST) and significantly (p<0.05) increases the contents of GABA neurotransmitter in hippocampus homogenates. The present study adds a positive implication of quetiapine, as an antipsychotic drug, on both the immobility and the reduction of GABA content in hippocampus of albino rats exposed restraint model for 21 days.

Background: General anesthetics potentiating γ-aminobutyric acid (GABA)–mediated signaling are known to induce a persistent
decrement in excitatory synapse number in the cerebral cortex when applied during early postnatal development, while
an opposite action is produced at later stages. Here, the authors test the hypothesis that the effect of general anesthetics on
synaptogenesis depends upon the efficacy of GABA receptor type A (GABAA)–mediated inhibition controlled by the developmental
up-regulation of the potassium-chloride (K-Cl) cotransporter 2 (KCC2).
Methods: In utero electroporation of KCC2 was used to prematurely increase the efficacy of (GABAA)–mediated inhibition
in layer 2/3 pyramidal neurons in the immature rat somatosensory cortex. Parallel experiments with expression of the inwardrectifier
potassium channel Kir2.1 were done to reduce intrinsic neuronal excitability. The effects of these genetic manipulations
(n = 3 to 4 animals per experimental group) were evaluated using iontophoretic injection of Lucifer Yellow (n = 8 to 12
cells per animal). The total number of spines analyzed per group ranged between 907 and 3,371.
Results: The authors found a robust effect of the developmental up-regulation of KCC2–mediated Cl− transport on the agedependent
action of propofol on dendritic spines. Premature expression of KCC2, unlike expression of a transport-inactive
KCC2 variant, prevented a propofol-induced decrease in spine density. In line with a reduction in neuronal excitability, the
above result was qualitatively replicated by overexpression of Kir2.1.
Conclusions: The KCC2–dependent developmental increase in the efficacy of GABAA–mediated inhibition is a major determinant
of the age-dependent actions of propofol on dendritic spinogenesis.

GABA concentrations in the cortex are highly correlated with a measure of visual behavioral inhibition, so that a higher concentration of GABA in the visual cortex predicts better performance in the orientation specific surround suppression (OSSS) test. I suggest using this behavioral-psychophysical test, already contrasted for the GABAergic hypothesis of schizophrenia using neuroimaging techniques such as magnetic resonance spectroscopy (MRS), and significantly correlated with the concentrations of GABA at the cortical level, in order to keep on studying these deficits in the synthesis of GABA in other mental diseases related with cortical inhibition as Alzheimer's disease.

In this study we show that single, physiologically-active and non-convulsive doses of the three GABA(B) receptor antagonists CGP 36742, CGP 56433A and CGP 56999A increase NGF and BDNF mRNA levels by 200-400% and protein levels by 200-250% in rat neocortex, hippocampus as well as spinal cord. In all areas examined the increase in NGF protein preceded that of BDNF. Peak levels of both neurotrophins are transient and occur between 24 and 72 h, depending on the region. In contrast, NT-3 protein concentrations in the neocortex and hippocampus were decreased significantly to 50% of control values within 48-96 h. The decrease in the spinal cord was less than 30% and did not reach significant levels. These data clearly demonstrate that GABA(B) receptor antagonists induce a specific neurotrophin expression in the central nervous system at physiologically relevant doses, as opposed to the extreme conditions of seizure paradigms. The results are in line with the concept that neuronal neurotrophin synthesis and release in brain are controlled by afferent nerve activity. GABA(B) receptor antagonists could therefore be a valuable new approach to selectively increase endogenous neurotrophin levels in the central nervous system.

Recent experimental evidence on the clustering of glutamate and GABA transporters on astrocytic processes surrounding synaptic terminals pose the question of the functional relevance of the astrocytes in the regulation of neural activity. In this perspective, we introduce a new computational model that embeds recent findings on neuron–astrocyte coupling at the mesoscopic scale intra- and inter-layer local neural circuits. The model consists of a mass model for the neural compartment and an astrocyte compartment which controls dynamics of extracellular glutamate and GABA concentrations. By arguments based on bifurcation theory, we use the model to study the impact of deficiency of astrocytic glutamate and GABA uptakes on neural activity. While deficient astrocytic GABA uptake naturally results in increased neuronal inhibition, which in turn results in a decreased neuronal firing, deficient glutamate uptake by astrocytes may either decrease or increase neuronal firing either transiently or permanently. Given the relevance of neuronal hyperexcitability (or lack thereof) in the brain pathophysiology, we provide biophysical conditions for the onset identifying different physiologically relevant regimes of operation for astrocytic uptake transporters.

PURPOSE:
Impaired GABAergic inhibition has been implicated in the pathophysiology of epilepsy. The possibility of a paradoxical excitatory effect of GABA in epilepsy has been suggested, but has not been investigated in vivo. We investigated pre- and post-synaptic GABAergic mechanisms in patients with idiopathic generalised epilepsy (IGE).
METHOD:
In 10 patients and 12 control subjects we explored short- and long-interval intracortical inhibition (SICI, LICI; post-synaptic GABAA and GABAB-mediated respectively) and long-interval intracortical facilitation (LICF; pre-synaptic disinhibition) using transcranial magnetic stimulation.

RESULTS:
While post-synaptic GABAB-mediated inhibition was unchanged in IGE (p=0.09), LICF was reduced compared to controls (controls: 141±17% of baseline; untreated patients: 107±12%, p=0.2; treated patients: 79±10%, p=0.003). GABAA-mediated inhibition was reduced in untreated patients (response amplitude 56±4% of baseline vs. 26±6% in controls, p=0.004) and normalised with treatment (37±12%, p=0.5 vs. controls). When measured during LICI, GABAA-mediated inhibition became excitatory in untreated IGE (response amplitude 120±10% of baseline, p=0.017), but not in treated patients.

CONCLUSION:
Pre- and post-synaptic GABA-mediated inhibitory mechanisms are altered in IGE. The findings lend in vivo support to evidence from experimental models and in vitro studies of human epileptic brain tissue that GABA may have a paradoxical excitatory role in ictogenesis.

Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Locomotor stimulation induced in mice by morphine and amphetamine was antagonized by pretreatment with ?,-butyrolactone (GBL) and aminooxyacetic acid (AOAA) at doses which had little effect on saline treated animals. The effects of morphine and AOAA on the turnover of brain catecholamines (CA) were determined by measuring both the accumulation of dopa after inhibition of central aromatic L-amino acid decarboxylase and by measuring the depletion of noradrenaline (NA) after inhibition of tyrosine hydroxylase by a-methyltyrosine (a-MT). Morphine and AOAA were found to have opposite effects on CA turnover, i.e. morphine caused an increase and AOAA, a decrease. AOAA also antagonized the morphineinduced increase in CA turnover. These data might suggest that the well documented ability of GABAergic drugs to inhibit the firing of DAcontaining neurons may be of importance in explaining the present findings. However, the locomotor stimulation induced by the directly-acting CA agonists, apomorphine and clonidine a~er pretreatment with reserpine and * Present address: 18 :'~ 254 J. Cott and J. Engel: a-MT was also inhibited by the GABAergic drugs. It is therefore concluded that the suppressant effects of the GABAergic agents on hypermotility are not solely mediated by their effects on presynaptic CA mechanisms, but also by a postsynaptic inhibition at some point beyond the CA neurons.

Continuous theta burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation protocol that can inhibit human motor cortex (M1) excitability and impair movement for Յ1 h. While offering valuable insights into brain function and potential therapeutic benefits, these neuroplastic effects are highly variable between individuals. The source of this variability, and the electrophysiological mechanisms underlying the inhibitory after-effects, are largely unknown. In this regard, oscillatory activity at beta frequency (15-35 Hz) is of particular interest as it is elevated in motor disorders such as Parkinson's disease and modulated during the generation of movements. Here, we used a source-level magnetoencephalography approach to investigate the hypothesis that the presence of neuroplastic effects following cTBS is associated with concurrent changes in oscillatory M1 beta activity. M1 cortices were localized with a synthetic aperture magnetometry beamforming analysis of visually cued index finger movements. Virtual electrode analysis was used to reconstruct the spontaneous and movement-related oscillatory activity in bilateral M1 cortices, before and from 10 to 45 min after cTBS. We demonstrate that 40 s of cTBS applied over left M1 reduced corticospinal excitability in the right index finger of 8/16 participants. In these responder participants only, cTBS increased the power of the spontaneous beta oscillations in stimulated M1 and delayed reaction times in the contralateral index finger. No further changes were observed in the latency or power of movement-related beta oscillations. These data provide insights into the electrophysiological mechanisms underlying cTBS-mediated impairment of motor function and demonstrate the association between spontaneous oscillatory beta activity in M1 and the inhibition of motor function.

Rationale: The benzodiazepine, lorazepam enhances the potential for inhibitory GABAA (-aminobutyric acid) synapses in the cortex to stabilize postsynaptic, excitatory activity by synchronizing discharge rates at frequencies of around 40 Hz. Treatment with lorazepam also affects contour integration processes, suggesting GABAA-mediated synchronization plays a role in visuo-spatial organization. This conclusion is supported by other physiological studies that link visual feature integration with neuronal synchronization.
Objectives: One experiment was conducted to assess variations in dynamic figural priming as a result of lorazepam administration.
Methods: Observers were presented a modified version of a figural priming paradigm designed to investigate the effects of dynamic synchronization upon visual feature integration. The priming paradigm consisted of premask crosses presented in square arrangement within the same phase of a multiphase premask matrix oscillating at 40 Hz. Observers responded to a subsequently presented target square. The modification consisted of line elements presented at various distances relative to the unspecified extension of the lines making up the premask crosses. It was expected that priming effects would be enhanced for lines terminating close to the unspecified extension but only following administration of lorazepam.
Results: As anticipated priming was enhanced substantially when the premask crosses flickered around static lines that terminated adjacent to the unspecified extension between the premask crosses. This effect was maximal following treatment with lorazepam.
Conclusions: This finding supports the idea that GABAA-enhanced inhibitory synchronization mediates continuity coding during early visual processing.

The temporal embryonic origins of cortical GABA neurons are critical for their specialization. In the neonatal hippocampus, GABA cells born the earliest (ebGABAs) operate as 'hubs' by orchestrating population synchrony. However, their adult fate remains largely unknown. To fill this gap, we have examined CA1 ebGABAs using a combination of electrophysiology, neurochemical analysis, optogenetic connectivity mapping as well as ex vivo and in vivo calcium imaging. We show that CA1 ebGABAs not only operate as hubs during development, but also maintain distinct morpho-physiological and connectivity profiles, including a bias for long-range targets and local excitatory inputs. In vivo, ebGABAs are activated during loco-motion, correlate with CA1 cell assemblies and display high functional connectivity. Hence, ebGABAs are specified from birth to ensure unique functions throughout their lifetime. In the adult brain, this may take the form of a long-range hub role through the coordination of cell assemblies across distant regions.

Abnormal circadian rhythms and circadian genes are strongly associated with several psychiatric disorders. Neuronal PAS Domain Protein 2 (NPAS2) is a core component of the molecular clock that acts as a transcription factor and is highly expressed in reward-and stress-related brain regions such as the striatum. However, the mechanism by which NPAS2 is involved in mood-related behaviors is still unclear. We measured anxiety-like behaviors in mice with a global null mutation in Npas2 (Npas2 null mutant mice) and found that Npas2 null mutant mice exhibit less anxiety-like behavior than their wild-type (WT) littermates (in elevated plus maze, light/dark box and open field assay). We assessed the effects of acute or chronic stress on striatal Npas2 expression, and found that both stressors increased levels of Npas2. Moreover, knockdown of Npas2 in the ventral striatum resulted in a similar reduction of anxiety-like behaviors as seen in the Npas2 null mutant mouse. Additionally, we identified Gabra genes as transcriptional targets of NPAS2, found that Npas2 null mutant mice exhibit reduced sensitivity to the GABAa positive allosteric modulator, diazepam and that knockdown of Npas2 reduced Gabra1 expression and response to diazepam in the ventral striatum. These results: (1) implicate Npas2 in the response to stress and the development of anxiety; and (2) provide functional evidence for the regulation of GABAergic neurotransmission by NPAS2 in the ventral striatum.