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Author

Santhosh Sethuramanujam

Other affiliations: University at Buffalo
Bio: Santhosh Sethuramanujam is an academic researcher from University of Victoria. The author has contributed to research in topics: Retina & Excitatory postsynaptic potential. The author has an hindex of 8, co-authored 18 publications receiving 294 citations. Previous affiliations of Santhosh Sethuramanujam include University at Buffalo.

Papers
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Journal ArticleDOI
TL;DR: It is reported that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate.
Abstract: As with other retinal cell types, retinal ganglion cells (RGCs) arise from multipotent retinal progenitor cells (RPCs), and their formation is regulated by a hierarchical gene-regulatory network (GRN). Within this GRN, three transcription factors—atonal homolog 7 (Atoh7), POU domain, class 4, transcription factor 2 (Pou4f2), and insulin gene enhancer protein 1 (Isl1)—occupy key node positions at two different stages of RGC development. Atoh7 is upstream and is required for RPCs to gain competence for an RGC fate, whereas Pou4f2 and Isl1 are downstream and regulate RGC differentiation. However, the genetic and molecular basis for the specification of the RGC fate, a key step in RGC development, remains unclear. Here we report that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate. The RGCs thus formed are largely normal in gene expression, survive to postnatal stages, and are physiologically functional. Our results indicate that Pou4f2 and Isl1 compose a minimally sufficient regulatory core for the RGC fate. We further conclude that during development a core group of limited transcription factors, including Pou4f2 and Isl1, function downstream of Atoh7 to determine the RGC fate and initiate RGC differentiation.

91 citations

Journal ArticleDOI
15 Jun 2016-Neuron
TL;DR: It is found that ACh initiates responses to motion in natural scenes or under low-contrast conditions, and mixed transmission plays a central role in shaping directional responses of DSGCs.

71 citations

Journal ArticleDOI
08 Apr 2015-Neuron
TL;DR: It is demonstrated that increasing ambient illumination leads to the recruitment of GABAergic wide-field amacrine cells (WACs) endowing the DS circuit with an additional feature: size selectivity, which permits high-fidelity direction coding over a range of ambient light levels, over which sizeSelectivity is adjusted.

65 citations

Journal ArticleDOI
TL;DR: In dorsal root ganglion neurons, loxapine was found to behave as an opener of native KNa channels and to increase the rheobase of action potential.
Abstract: Sodium-activated potassium (K(Na)) channels have been suggested to set the resting potential, to modulate slow after-hyperpolarizations, and to control bursting behavior or spike frequency adaptation (Trends Neurosci 28:422-428, 2005). One of the genes that encodes K(Na) channels is called Slack (Kcnt1, Slo2.2). Studies found that Slack channels were highly expressed in nociceptive dorsal root ganglion neurons and modulated their firing frequency (J Neurosci 30:14165-14172, 2010). Therefore, Slack channel openers are of significant interest as putative analgesic drugs. We screened the library of pharmacologically active compounds with recombinant human Slack channels expressed in Chinese hamster ovary cells, by using rubidium efflux measurements with atomic absorption spectrometry. Riluzole at 500 μM was used as a reference agonist. The antipsychotic drug loxapine and the anthelmintic drug niclosamide were both found to activate Slack channels, which was confirmed by using manual patch-clamp analyses (EC(50) = 4.4 μM and EC(50) = 2.9 μM, respectively). Psychotropic drugs structurally related to loxapine were also evaluated in patch-clamp experiments, but none was found to be as active as loxapine. Loxapine properties were confirmed at the single-channel level with recombinant rat Slack channels. In dorsal root ganglion neurons, loxapine was found to behave as an opener of native K(Na) channels and to increase the rheobase of action potential. This study identifies new K(Na) channel pharmacological tools, which will be useful for further Slack channel investigations.

30 citations

Journal ArticleDOI
04 Feb 2019-eLife
TL;DR: It is demonstrated that direction selectivity in downstream ganglion cells remains remarkably unaffected when starburst dendrites are rendered non-directional, using a novel strategy combining a conditional GABAA α2 receptor knockout mouse with optogenetics.
Abstract: In the mammalian retina, direction-selectivity is thought to originate in the dendrites of GABAergic/cholinergic starburst amacrine cells, where it is first observed. However, here we demonstrate that direction selectivity in downstream ganglion cells remains remarkably unaffected when starburst dendrites are rendered non-directional, using a novel strategy combining a conditional GABAA α2 receptor knockout mouse with optogenetics. We show that temporal asymmetries between excitation/inhibition, arising from the differential connectivity patterns of starburst cholinergic and GABAergic synapses to ganglion cells, form the basis for a parallel mechanism generating direction selectivity. We further demonstrate that these distinct mechanisms work in a coordinated way to refine direction selectivity as the stimulus crosses the ganglion cell’s receptive field. Thus, precise spatiotemporal patterns of inhibition and excitation that determine directional responses in ganglion cells are shaped by two ‘core’ mechanisms, both arising from distinct specializations of the starburst network.

29 citations


Cited by
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Journal ArticleDOI
13 Nov 2020-Science
TL;DR: A pooled approach using three levels of combinatorial indexing to examine the single-cell gene expression and chromatin landscapes from 15 organs in fetal samples, which generates comprehensive atlases of early human development.
Abstract: The gene expression program underlying the specification of human cell types is of fundamental interest. We generated human cell atlases of gene expression and chromatin accessibility in fetal tissues. For gene expression, we applied three-level combinatorial indexing to >110 samples representing 15 organs, ultimately profiling ~4 million single cells. We leveraged the literature and other atlases to identify and annotate hundreds of cell types and subtypes, both within and across tissues. Our analyses focused on organ-specific specializations of broadly distributed cell types (such as blood, endothelial, and epithelial), sites of fetal erythropoiesis (which notably included the adrenal gland), and integration with mouse developmental atlases (such as conserved specification of blood cells). These data represent a rich resource for the exploration of in vivo human gene expression in diverse tissues and cell types.

372 citations

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22 May 2014

270 citations

Journal ArticleDOI
07 Jul 2016-Nature
TL;DR: A detailed connectomic reconstruction of SAC circuitry in mouse retina is presented and two previously unknown features of synapse distributions along SAC dendrite are described: input and output synapses are segregated, with inputs restricted to proximal dendrites; and the distribution of inhibitory inputs is fundamentally different from that observed in rabbit retina.
Abstract: Directionally tuned signalling in starburst amacrine cell (SAC) dendrites lies at the heart of the circuit that detects the direction of moving stimuli in the mammalian retina. The relative contributions of intrinsic cellular properties and network connectivity to SAC direction selectivity remain unclear. Here we present a detailed connectomic reconstruction of SAC circuitry in mouse retina and describe two previously unknown features of synapse distributions along SAC dendrites: input and output synapses are segregated, with inputs restricted to proximal dendrites; and the distribution of inhibitory inputs is fundamentally different from that observed in rabbit retina. An anatomically constrained SAC network model suggests that SAC–SAC wiring differences between mouse and rabbit retina underlie distinct contributions of synaptic inhibition to velocity and contrast tuning and receptive field structure. In particular, the model indicates that mouse connectivity enables SACs to encode lower linear velocities that account for smaller eye diameter, thereby conserving angular velocity tuning. These predictions are confirmed with calcium imaging of mouse SAC dendrites responding to directional stimuli.

165 citations

Journal ArticleDOI
18 Nov 2015
TL;DR: It is proposed that the apparent complexity of retinal computation derives from a straightforward mechanism-a dynamic balance of synaptic excitation and inhibition regulated by use-dependent synaptic depression-applied differentially to the parallel pathways that feed ganglion cells.
Abstract: The mammalian retina is an important model system for studying neural circuitry: Its role in sensation is clear, its cell types are relatively well defined, and its responses to natural stimuli—light patterns—can be studied in vitro. To solve the retina, we need to understand how the circuits presynaptic to its output neurons, ganglion cells, divide the visual scene into parallel representations to be assembled and interpreted by the brain. This requires identifying the component interneurons and understanding how their intrinsic properties and synapses generate circuit behaviors. Because the cellular composition and fundamental properties of the retina are shared across species, basic mechanisms studied in the genetically modifiable mouse retina apply to primate vision. We propose that the apparent complexity of retinal computation derives from a straightforward mechanism—a dynamic balance of synaptic excitation and inhibition regulated by use-dependent synaptic depression—applied differentially to the p...

143 citations