As with other retinal cell types, ganglion cells (RGCs) arise from multipotent progenitor (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, factor 2 (Pou4f2), insulin gene enhancer protein 1 (Isl1)--occupy key node positions at two different stages of RGC development. Atoh7 upstream required for RPCs to gain competence an fate, whereas Pou4f2 Isl1 are...

Abstract In many parts of the central nervous system, including retina, it is unclear whether cholinergic transmission mediated by rapid, point-to-point synaptic mechanisms, or slower, broad-scale ‘non-synaptic’ mechanisms. Here, we characterized ultrastructural features connections between direction-selective starburst amacrine cells and downstream ganglion in an existing serial electron microscopy data set, as well their functional properties using electrophysiology two-photon...

The asymmetric summation of kinetically distinct glutamate inputs across the dendrites retinal ‘starburst’ amacrine cells is one several mechanisms that have been proposed to underlie their direction-selective properties, but experimentally verifying input kinetics has a challenge. Here, we used two-photon sensor (iGluSnFR) imaging directly measure individual starburst dendrites. We found signals measured from proximal were relatively sustained compared those distal These differences...

ABSTRACT Direction selectivity is a fundamental feature in the visual system. In retina, direction independently computed by ON and OFF circuits. However, advantages of extracting directional information from these two independent circuits are unclear. To gain insights, we examined ON–OFF direction‐selective ganglion cells (DSGCs), which recombine signals both Specifically, investigated dendritic architecture neurons with premise that asymmetries will provide insights into function....

In the mammalian retina, direction-selectivity is thought to originate in dendrites of GABAergic/cholinergic starburst amacrine cells, where it first observed. However, here we demonstrate that direction selectivity downstream ganglion cells remains remarkably unaffected when are rendered non-directional, using a novel strategy combining conditional GABAA α2 receptor knockout mouse with optogenetics. We show temporal asymmetries between excitation/inhibition, arising from differential...

Recent studies indicate that the precise timing and location of excitation inhibition (E/I) within active dendritic trees can significantly impact neuronal function. How synaptic inputs are functionally organized at subcellular level in intact circuits remains unclear. To address this issue, we took advantage retinal direction-selective ganglion cell circuit, where directionally tuned is known to shape non-directional excitatory signals. We combined two-photon calcium imaging with genetic,...

Sodium-activated potassium (K_Na) channels have been suggested to set the resting potential, modulate slow after-hyperpolarizations, and control bursting behavior or spike frequency adaptation (<i>Trends Neurosci</i><b>28:</b>422–428, 2005). One of genes that encodes K_Na is called <i>Slack</i> (<i>Kcnt1</i>, <i>Slo2.2</i>). Studies found Slack were highly expressed in nociceptive dorsal root ganglion neurons modulated their firing (<i>J Neurosci</i><b>30:</b>14165–14172,...

In the retina, ON starburst amacrine cells (SACs) play a crucial role in direction-selective circuit, but sources of inhibition that shape their response properties remain unclear. Previous studies demonstrate ∼95% inhibitory synapses are GABAergic, yet we find light-evoked currents measured SACs predominantly glycinergic. Glycinergic is extremely slow, relying on non-canonical glycine receptors containing α4 subunits, and driven by both OFF retinal pathways. These attributes enable inputs...

Inherited retinal degenerations (IRDs) are characterized by the progressive loss of photoreceptors and represent one most prevalent causes blindness among working-age populations. Cyclic nucleotide dysregulation is a common pathological feature linked to numerous forms IRD, yet precise mechanisms through which this contributes photoreceptor death remain elusive. Here we demonstrate that cAMP induced upregulation dependence receptor neogenin in retina. Neogenin levels were also elevated both...

Starburst amacrine cells release GABA and ACh. This study explores the coordinated function of starburst-mediated cholinergic excitation GABAergic inhibition to bistratified retinal ganglion cells, predominantly direction-selective (DSGCs). In rat retina, under our recording conditions, starbursts were found provide major excitatory drive a sub-population whose dendrites co-stratify with starburst (putative DSGCs). mouse recordings from genetically identified DSGCs at physiological...

Glutamate release at bipolar to ganglion cell synapses activates NMDA and AMPA/kainic acid (KA) ionotropic glutamate receptors. Their relative strength determines the output signals of retina. We found that this balance is tightly regulated by presynaptic inhibition preferentially suppresses receptor (NMDAR) activation. In transient ON-OFF neurons, block GABA glycine feedback enhanced total NMDAR charge 35-fold in ON response 9-fold OFF compared with a 1.7-fold enhancement AMPA/KA Blocking...

Abstract Acetylcholine (ACh) is a key neurotransmitter that plays diverse roles in many parts of the central nervous system, including retina. However, assessing precise spatiotemporal dynamics ACh technically challenging and whether transmits signals via rapid, point-to-point synaptic mechanisms, or broader-scale ‘non-synaptic’ mechanisms has been difficult to ascertain. Here, we examined properties cholinergic transmission at individual contacts made between direction-selective starburst...

One general categorization of retinal ganglion cells is to segregate them into tonically or phasically responding neurons, each conveying discrete aspects the visual scene. Although best identified in output signals retina, this distinction initiated at first synapse: between photoreceptors and dendrites bipolar cells. In study we found that synapses also contribute separate these pathways. Both transient sustained can produce maintained spike activity, but cell glutamate release exhibits a...

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22763-3

SUMMARY Recent studies indicate that the precise timing and location of excitation inhibition (E/I) within active dendritic trees can significantly impact neuronal function. How excitatory inhibitory inputs are functionally organized at subcellular level in intact circuits remains unclear. To address this issue, we took advantage retinal direction-selective ganglion cell circuit, which directionally tuned GABAergic input arising from starburst amacrine cells shape responses. We combined...

S ummary Retinal ON starburst amacrine cells (SACs) play a critical role in computing stimulus direction, partly service of image stabilization by optokinetic nystagmus. SAC responses are sculpted rich GABAergic innervation, mostly from neighbouring SACs. Surprisingly, however, we find that glycinergic narrow field (NACs) serve as their dominant source inhibition during sustained activity. Although NAC inputs constitute only ∼5% inhibitory synapses to SACs, distinct input patterns enable...

S ummary In the mammalian retina, asymmetric inhibitory signals arising from direction-selective dendrites of GABAergic/cholinergic starburst amacrine cells are thought to be crucial for originating direction selectivity. Contrary this notion, however, we found that selectivity in downstream ganglion remains remarkably unaffected when output is rendered non-directional (using a novel strategy combining conditional GABA A α2 receptor knockout mouse with optogenetics). We show temporal...