Sammy Lee

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Dara M Cannon

University of Galway

César Lima

ISCTE - University Institute of Lisbon (ISCTE-IUL)

Dr. Artur C Jaschke

ArtEZ Institute of the Arts

Alessia Tessari

Università di Bologna

Sanja Budisavljevic

Università degli Studi di Padova

Viacheslav Kuleshov

Stockholm University

Amir Poreh

Cleveland State University

Juliana Sbicigo

Universidade Federal do Rio Grande do Sul

Panagiotis Kourtesis

The American College of Greece Deree College

Erik Cattrysse

Vrije Universiteit Brussel

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Papers by Sammy Lee

Satb1 expression in retinal ganglion cells of marmosets, macaques and humans

Journal of Comparative Neurology

Melanopsin and calbindin immunoreactivity in the inner retina of humans and marmosets

Visual Neuroscience

In primate retina, the calcium-binding protein calbindin is expressed by a variety of neurons inc... more In primate retina, the calcium-binding protein calbindin is expressed by a variety of neurons including cones, bipolar cells, and amacrine cells but it is not known which type(s) of cell express calbindin in the ganglion cell layer. The present study aimed to identify calbindin-positive cell type(s) in the amacrine and ganglion cell layer of human and marmoset retina using immunohistochemical markers for ganglion cells (RBPMS and melanopsin) and cholinergic amacrine (ChAT) cells. Intracellular injections following immunolabeling was used to reveal the morphology of calbindin-positive cells. In human retina, calbindin-labeled cells in the ganglion cell layer were identified as inner and outer stratifying melanopsin-expressing ganglion cells, and ON ChAT (starburst amacrine) cells. In marmoset, calbindin immunoreactivity in the ganglion cell layer was absent from ganglion cells but present in ON ChAT cells. In the inner nuclear layer of human retina, calbindin was found in melanopsin-...

Random spatial patterning of cone bipolar cell mosaics in the mouse retina

Visual neuroscience, 2017

Retinal bipolar cells spread their dendritic arbors to tile the retinal surface, extending them t... more Retinal bipolar cells spread their dendritic arbors to tile the retinal surface, extending them to the tips of the dendritic fields of their homotypic neighbors, minimizing dendritic overlap. Such uniform nonredundant dendritic coverage of these populations would suggest a degree of spatial order in the properties of their somal distributions, yet few studies have examined the patterning in retinal bipolar cell mosaics. The present study examined the organization of two types of cone bipolar cells in the mouse retina, the Type 2 cells and the Type 4 cells, and compared their spatial statistical properties with those of the horizontal cells and the cholinergic amacrine cells, as well as to random simulations of cells matched in density and constrained by soma size. The Delauney tessellation of each field was computed, from which nearest neighbor distances and Voronoi domain areas were extracted, permitting a calculation of their respective regularity indexes (RIs). The spatial autoco...

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Suppl Neuron 2013

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Identification of AII amacrine, displaced amacrine and bistratified ganglion cell types in human retina with antibodies against calretinin

The Journal of comparative neurology, Jan 6, 2015

Antibodies against calretinin are markers for one type of rod pathway interneurone (AII amacrine ... more Antibodies against calretinin are markers for one type of rod pathway interneurone (AII amacrine cell) in the retina of some but not all mammalian species. The AII cells play a crucial role in night-time (scotopic) vision and have been proposed as a target for optogenetic restoration of vision in retinal disease. In the present study we aimed to characterize the AII cells in human retina. Post mortem human donor eyes were obtained with ethical approval and processed for calretinin immunofluorescence. Calretinin positive somas in the inner nuclear and the ganglion cell layer were filled with the lipophilic dye DiI. The large majority (over 80%) of calretinin immunoreactive cells is located in the inner nuclear layer, is immunopositive for glycine transporter 1 and shows the typical morphology of AII amacrine cells. In addition a small proportion of calretinin positive cells in the inner nuclear layer and in the ganglion cell layer is glutamic acid decarboxylase positive and shows the...

Morphology and connectivity of the small bistratified A8 amacrine cell in the mouse retina

The Journal of comparative neurology, Jan 29, 2015

Amacrine cells comprise ∼30 morphological types in the mammalian retina. The synaptic connectivit... more Amacrine cells comprise ∼30 morphological types in the mammalian retina. The synaptic connectivity and function of a few GABAergic wide-field amacrine cells have recently been studied, however, with the exception of the rod pathway-specific AII amacrine cell the connectivity of glycinergic small-field amacrine cells has not been investigated in the mouse retina. Here, we studied the morphology and connectivity pattern of the small-field A8 amacrine cell. A8 cells in mouse retina are bistratified with lobular processes in the ON sublamina and arboreal dendrites in the OFF sublamina of the inner plexiform layer. The distinct bistratified morphology was first visible at postnatal day 8, reaching the adult shape at P13, around eye opening. The connectivity of A8 cells to bipolar cells and ganglion cells was studied by double and triple immunolabeling experiments using various cell markers combined with synaptic markers. Our data suggest that A8 amacrine cells receive glutamatergic input...

Synaptic connectivity of a diffuse dipolar cell type in the inner primate retina

Bipolar input to melanopsin containing ganglion cells in primate retina

Visual Neuroscience, 2011

Two morphological types of melanopsin-expressing ganglion cells have been described in primate re... more Two morphological types of melanopsin-expressing ganglion cells have been described in primate retina. Both types show intrinsic light responses as well as rod- and cone-driven ON-type responses. Outer stratifying cells have their dendrites close to the inner nuclear layer (OFF sublamina); inner stratifying cells have their dendrites close to the ganglion cell layer (ON sublamina). Both inner and outer stratifying cells receive synaptic inputviaribbon synapses, but the bipolar cell types providing this input have not been identified. Here, we addressed the question whether the diffuse (ON) cone bipolar type DB6 and/or rod bipolar cells contact melanopsin-expressing ganglion cells. Melanopsin containing ganglion cells in marmoset (Callithrix jacchus) and macaque (Macaca fascicularis) retinas were identified immunohistochemically; DB6 cells were labeled with antibodies against the carbohydrate epitope CD15, rod bipolar cells were labeled with antibodies against protein kinase C, and p...

Apoptosis Regulates ipRGC Spacing Necessary for Rods and Cones to Drive Circadian Photoentrainment

Neuron, 2013

The retina consists of ordered arrays of individual types of neurons for processing vision. Here,... more The retina consists of ordered arrays of individual types of neurons for processing vision. Here, we show that such order is necessary for intrinsically photosensitive retinal ganglion cells (ipRGCs) to function as irradiance detectors. We found that during development, ipRGCs undergo proximity-dependent Bax-mediated apoptosis. Bax mutant mice exhibit disrupted ipRGC spacing and dendritic stratification with an increase in abnormally localized synapses. ipRGCs are the sole conduit for light input to circadian photoentrainment, and either their melanopsin-based photosensitivity or ability to relay rod/cone input is sufficient for circadian photoentrainment. Remarkably, the disrupted ipRGC spacing does not affect melanopsin-based circadian photoentrainment but severely impairs rod/cone-driven photoentrainment. We demonstrate reduced rod/cone-driven cFos activation and electrophysiological responses in ipRGCs, suggesting that impaired synaptic input to ipRGCs underlies the photoentrainment deficits. Thus, for irradiance detection, developmental apoptosis is necessary for the spacing and connectivity of ipRGCs that underlie their functioning within a neural network.

Advances in understanding circuits serving colour vision

Journal of Vision, 2010

The midget-parvocellular pathway of marmoset retina: A quantitative light microscopic study

The Journal of Comparative Neurology, 2008

The midget-parvocellular pathway in foveal retina of primates shows a &amp;amp;amp;amp;amp;am... more The midget-parvocellular pathway in foveal retina of primates shows a &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;private line&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; (one-to-one) connectivity with cone photoreceptors. The connectivity of this pathway outside the fovea is not well understood. Here, we studied the population of OFF midget bipolar cells across the retinae of marmoset monkeys (Callithrix jacchus) by using light microscopy. Cone pedicles were labeled with peanut agglutinin, OFF midget bipolar cells were labeled with antibodies against CD15, and midget ganglion cells were retrogradely labeled from the lateral geniculate nucleus and subsequently photofilled. Each midget bipolar cell contacts a single cone in foveal retina, but outside the fovea midget bipolar cells contact multiple cones: one to two cones at 1 mm ( approximately 8 degrees); three to four cones at 3-4 mm ( approximately 25 degrees); and five or more cones beyond 6 mm (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50 degrees). Throughout this eccentricity range, all medium (M) and long (L) wavelength sensitive cones make similar number of contacts with midget bipolar cells, but short wavelength sensitive (S) cones make little or no contact. By calculating the numerical convergence between midget bipolar and midget ganglion cells, we estimate that midget ganglion cells receive input from up to 25 cones at approximately 5 degrees, and from more than 65 cones at approximately 50 degrees. No obvious differences were seen between the retinae of animals with di- or trichromatic color vision. The finding that the one-to-one connectivity is restricted to the fovea predicts that in marmosets spectral mixing of M/L cone inputs will occur peripheral to 10 degrees of visual angle.

S-cone connections of the diffuse bipolar cell type DB6 in macaque monkey retina

The Journal of Comparative Neurology, 2004

Previous studies of primate retinae have shown that diffuse bipolar (DB) cells contact all the co... more Previous studies of primate retinae have shown that diffuse bipolar (DB) cells contact all the cones in their dendritic field, suggesting there is no spectral selectivity in the functional input to DB cells. However, since short-wavelength sensitive (S) cones make up less than 10% of the total cone population, specialized connectivity with Scones is difficult to detect. In the present study, the Scone connectivity of a subtype of DB cells, the DB6 cell, was studied in macaque monkey retina. Pieces of macaque retina were processed with antibodies to CD15 to stain DB6 cells and antibodies to the Scone opsin to identify Scones. Immunoreactivity was visualized using immunoperoxidase or immunofluorescence. Some preparations were additionally processed with peanut agglutinin coupled to fluorescein to reveal medium-and long-wavelength sensitive (M/L) cones. The preparations were analyzed using conventional and deconvolution light microscopy. The majority of DB6 cells had one or two Scones in their dendritic field and the majority of Scones were located in the dendritic field of DB6 cells. On average, 80% of the Scones and 81% of the M/L cones contacted DB6 cells. The average number of dendritic terminals at cone pedicles did not differ between the cone types. However, the total number of DB6 dendritic terminals receiving input from M/L-cone pedicles was about eight times higher than the total number of dendritic terminals at Scone pedicles. In conclusion, DB6 cells make indiscriminate contact with all cone types, but receive their major input from M/L-cones and thus carry a "Yellow-ON" spectral signal.

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Connections of diffuse bipolar cells in primate retina are biased against S-cones

The Journal of Comparative Neurology, 2007

In mammalian retina, each diffuse bipolar type stratifies in a distinct layer of the inner plexif... more In mammalian retina, each diffuse bipolar type stratifies in a distinct layer of the inner plexiform layer. Thus, different types of bipolar cells provide output to distinct visual pathways. Here, the question of whether diffuse bipolar cell types differ with respect to their contacts with short wavelength-sensitive (S-) cones was investigated in the retinas of a New World monkey, Callithrix jacchus, and an Old World monkey, Macaca fascicularis. Subpopulations of OFF bipolar cells were labeled with antibodies to the glutamate transporter Glt-1 and ON bipolar cells were labeled with antibodies to the alpha subunit of the Go protein (Goalpha). Two types of diffuse ON bipolar cells, DB4 and DB6, were identified with antibodies to protein kinase Calpha and CD15, respectively. Cone pedicles were labeled either with peanut agglutinin coupled to fluorescein or with antibodies to the ribbon protein, C-terminus binding protein 2. We found that immunoreactivity for Glt-1 (OFF bipolar cells) is reduced at S-cones in comparison to medium/long wavelength-sensitive (M/L-) cones. Immunoreactivity for Goalpha (ON bipolar cells) is comparable at all cone types. Nearly all M/L-cone pedicles contact the diffuse ON bipolar types DB4 and DB6, but only between 60% and 75% of the S-cone pedicles make contact. Furthermore, the number of dendritic tips of DB4 and DB6 cells at S-cone pedicles is lower than that at M/L-cone pedicles. These results suggest that there is a bias in the S-cone connectivity of diffuse bipolar cells.

Synaptic connectivity of the diffuse bipolar cell type DB6 in the inner plexiform layer of primate retina

The Journal of Comparative Neurology, 2004

Diffuse bipolar cells in primate retina receive synaptic input from multiple cones and provide ou... more Diffuse bipolar cells in primate retina receive synaptic input from multiple cones and provide output to ganglion cells. Diffuse bipolar cells can be subdivided into six types (DB1-DB6) according to the stratification of their axon terminals in the inner plexiform layer, but their synaptic connectivity in the inner plexiform layer is not well understood. Here the stratification and synaptic connectivity of DB6 axon terminals were studied in the retinae of New World (marmoset) and Old World (macaque) monkeys. Immunohistochemical markers were applied to retinal sections. The sections were analyzed by confocal and deconvolution light microscopy as well as electron microscopy. The DB6 cells were identified with antibodies against CD15; rod bipolar cells were identified with antibodies against protein kinase C␣ (PKC␣); and AII amacrine cells were identified with antibodies against calretinin. The axons of DB6 and rod bipolar cells occupy distinct regions in stratum 5 of the inner plexiform layer. The distal processes of calretinin-labeled AII cells are usually closely associated with rod bipolar axons but sometimes also with DB6 axons. Pre-embedding immunoelectron microscopy showed that the vast majority (over 86%) of the synaptic output of DB6 cells is onto amacrine cell processes, whereas less than 14% goes to ganglion cell processes. In doublelabeled preparations DB6 axons occasionally made output onto calretinin-labeled amacrine processes. Thus it is possible that AII cells receive some input from DB6 cells.

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Neuronal clustering and fasciculation phenotype in Dscam- and Bax-deficient mouse retinas

The Journal of Comparative Neurology, 2012

Individual types of retinal neurons are distributed to minimize proximity to neighboring cells. M... more Individual types of retinal neurons are distributed to minimize proximity to neighboring cells. Many of these same cell types extend dendrites to provide coverage of the retinal surface. These two cardinal features of retinal mosaics are disrupted, for certain cell types, in mice deficient for the Down syndrome cell adhesion molecule, Dscam, exhibiting an aberrant clustering of somata and fasciculation of dendrites. The Dscam-mutant mouse retina also exhibits excess numbers of these same cell types. The present study compared these two features in Dscam-mutant retinas with the Bax-knockout retina, in which excess numbers of two of these cell types, the melanopsinpositive retinal ganglion cells (MRGCs) and the dopaminergic amacrine cells (DACs), are also present. Whole retinas were immunolabeled for both populations, and every labeled soma was plotted. For the MRGCs, we found a gene dosage effect for Dscam, with the Dscam+/retinas showing smaller increases in cell number, clustering and fasciculation. Curiously, Bax-/retinas, showing numbers of MRGCs intermediate to those found in the Dscam-/versus Dscam+/retinas, also had clustering and fasciculation phenotypes that were intermediate to retinas with those genotypes. DACs, by comparison, showed changes in both the Dscam-/and Bax-/retinas that did not correlate with their increases in DAC number. The fasciculation phenotype in the Dscam-/retina was particularly prominent despite only modest clustering. These results demonstrate that the somal clustering and fasciculation observed in the Dscam-mutant retina are not unique to Dscam-deficiency, and are manifested distinctively by different retinal cell-types.

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S-cones do not contribute to the OFF-midget pathway in the retina of the marmoset, Callithrix jacchus

European Journal of Neuroscience, 2005

It is well established that in primate retina both medium- and long-wavelength-sensitive cone typ... more It is well established that in primate retina both medium- and long-wavelength-sensitive cone types provide input to the midget-parvocellular pathway. The question, however, whether short-wavelength-sensitive (S or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;blue&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;) cones provide input to the OFF-division of the midget-parvocellular pathway is still controversial. In the present study, we investigated the connections of nearly 400 S-cones with OFF-midget bipolar cells in central and peripheral retina of a New World monkey, the marmoset. Horizontal sections or pieces of whole retinae were double-labelled with an antiserum to S-cone opsin to identify S-cones and antibodies to the cell adhesion molecule CD15 to identify OFF-midget bipolar cells. Peanut agglutinin coupled to a fluorescent tag was used to label the cone pedicles of all cone types. Peanut agglutinin was also used to distinguish S-cones from the other cone types. The sections were analysed with deconvolution microscopy. We found that nearly all pedicles of medium- and long-wavelength-sensitive cones are located opposite distinct dendritic clusters formed by OFF-midget bipolar cells. By contrast, the S-cone pedicles are not located opposite dendritic clusters. Instead, S-cones make sparse contacts with CD15-labelled processes. Some of these processes protruded from OFF-midget bipolar clusters, whereas others could be traced to a diffuse bipolar cell type. Thus, in the marmoset retina the midget-parvocellular system does not carry a blue-OFF signal.

Developmental plasticity of dendritic morphology and the establishment of coverage and connectivity in the outer retina

Developmental Neurobiology, 2011

Developing retinal neurons differentiate their distinctive dendritic morphologies through cell-in... more Developing retinal neurons differentiate their distinctive dendritic morphologies through cell-intrinsic instructions and cellular interactions within the local environment. This review examines the contributions of interactions with afferents and with homotypic neighbors upon the dendritic morphogenesis of retinal bipolar cells in four different mouse models that modulate the frequency of these interactions. Comparisons with horizontal cell differentiation are discussed, and differences between the dendritic plasticity within the outer versus inner plexiform layers are highlighted. Finally, the developmental plasticity of the bipolar and horizontal cells is considered in light of the natural variation in afferent and target cell number, ensuring a uniformity of coverage and connectivity across the retinal surface. © 2011 Wiley Periodicals, Inc. Develop Neurobiol, 2011.

S-Cone Connections of OFF Midget Bipolar Cells in the Retina of a New World Monkey

Homotypic Regulation of Neuronal Morphology and Connectivity in the Mouse Retina

The establishment of neuronal circuitry during development relies upon the action of cell-intrins... more The establishment of neuronal circuitry during development relies upon the action of cell-intrinsic mechanisms that specify neuronal form as well as plastic processes that require the transmission of neural activity between afferents and their targets. Here, we examine the role of interactions between neighboring like-type cells within the mouse retina upon neuronal differentiation and circuit formation. Two different genetically modified mouse models were used to modulate the density of homotypic neighbors, the Type 7 cone bipolar cells, without affecting the density of their afferents, the cone photoreceptors. We demonstrate a corresponding plasticity in dendritic field area when the density of Type 7 cone bipolar cells is elevated or reduced. In accord with this variation in dendritic field area across an invariant population of afferents, individual Type 7 cone bipolar cells are also shown to modulate the number of cone pedicles contacted without varying the number of contacts at each cone pedicle. Analysis of developing Type 7 cone bipolar cells reveals that the dendritic tiling present in maturity is achieved secondarily, after an initial stage of dendritic overlap, when the dendritic terminals are stratified at the level of the cone pedicles but are not localized to them. These results demonstrate a conspicuous developmental plasticity in neural circuit formation independent of neural activity, requiring homotypic interactions between neighboring cells that ultimately regulate connectivity within the retina.

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Characterization and synaptic connectivity of melanopsin-containing ganglion cells in the primate retina

by Jens Hannibal and Sammy Lee

European Journal of Neuroscience, 2007

Melanopsin is a photopigment expressed in retinal ganglion cells, which are intrinsically photose... more Melanopsin is a photopigment expressed in retinal ganglion cells, which are intrinsically photosensitive and are also involved in retinal circuits arising from rod and cone photoreceptors. This circuitry, however, is poorly understood. Here, we studied the morphology, distribution and synaptic input to melanopsin-containing ganglion cells in a New World monkey, the common marmoset (Callithrix jacchus). The dendrites of melanopsin-containing cells in marmoset stratify either close to the inner nuclear layer (outer stratifying), or close to the ganglion cell layer (inner stratifying). The dendritic fields of outer-stratifying cells tile the retina, with little overlap. However, the dendritic fields of outer-stratifying cells largely overlap with the dendritic fields of inner-stratifying cells. Thus, innerstratifying and outer-stratifying cells may form functionally independent populations. The synaptic input to melanopsin-containing cells was determined using synaptic markers (antibodies to C-terminal binding protein 2, CtBP2, for presumed bipolar synapses, and antibodies to gephyrin for presumed amacrine synapses). Both outer-stratifying and inner-stratifying cells show colocalized immunoreactive puncta across their entire dendritic tree for both markers. The density of CtBP2 puncta on inner dendrites was about 50% higher than that on outer dendrites. The density of gephyrin puncta was comparable for outer and inner dendrites but higher than the density of CtBP2 puncta. The inner-stratifying cells may receive their input from a type of diffuse bipolar cell (DB6). Our results are consistent with the idea that both outer and inner melanopsin cells receive bipolar and amacrine input across their dendritic tree.

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Satb1 expression in retinal ganglion cells of marmosets, macaques and humans

Journal of Comparative Neurology

Melanopsin and calbindin immunoreactivity in the inner retina of humans and marmosets

Visual Neuroscience

Random spatial patterning of cone bipolar cell mosaics in the mouse retina

Visual neuroscience, 2017

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Suppl Neuron 2013

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Identification of AII amacrine, displaced amacrine and bistratified ganglion cell types in human retina with antibodies against calretinin

The Journal of comparative neurology, Jan 6, 2015

Morphology and connectivity of the small bistratified A8 amacrine cell in the mouse retina

The Journal of comparative neurology, Jan 29, 2015

Synaptic connectivity of a diffuse dipolar cell type in the inner primate retina

Bipolar input to melanopsin containing ganglion cells in primate retina

Visual Neuroscience, 2011

Apoptosis Regulates ipRGC Spacing Necessary for Rods and Cones to Drive Circadian Photoentrainment

Neuron, 2013

Advances in understanding circuits serving colour vision

Journal of Vision, 2010

The midget-parvocellular pathway of marmoset retina: A quantitative light microscopic study

The Journal of Comparative Neurology, 2008

S-cone connections of the diffuse bipolar cell type DB6 in macaque monkey retina

The Journal of Comparative Neurology, 2004

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Connections of diffuse bipolar cells in primate retina are biased against S-cones

The Journal of Comparative Neurology, 2007

Synaptic connectivity of the diffuse bipolar cell type DB6 in the inner plexiform layer of primate retina

The Journal of Comparative Neurology, 2004

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Neuronal clustering and fasciculation phenotype in Dscam- and Bax-deficient mouse retinas

The Journal of Comparative Neurology, 2012

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S-cones do not contribute to the OFF-midget pathway in the retina of the marmoset, Callithrix jacchus

European Journal of Neuroscience, 2005

Developmental plasticity of dendritic morphology and the establishment of coverage and connectivity in the outer retina

Developmental Neurobiology, 2011

S-Cone Connections of OFF Midget Bipolar Cells in the Retina of a New World Monkey

Homotypic Regulation of Neuronal Morphology and Connectivity in the Mouse Retina

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Characterization and synaptic connectivity of melanopsin-containing ganglion cells in the primate retina

by Jens Hannibal and Sammy Lee

European Journal of Neuroscience, 2007

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