# Neural Circuits and Synapses for Early Visual Processing

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $413,446

## Abstract

The goal of this research program is to understand how visual information is encoded by synaptic interactions
within neural circuits of the retina. This proposal focuses on the mechanisms and roles for synaptic inhibition
mediated by retinal interneurons called amacrine cells. Amacrine cells are the retina's most diverse cell class
and the main drivers of functional diversity in retinal circuits: they influence visual processing through their
synapses with bipolar cell terminals (excitatory interneurons), ganglion cells (projection neurons), and other
amacrine cells. Despite their significance, only a few amacrine cell types have been studied in detail. Over the
previous grant period, we discovered and studied novel amacrine cell circuits. We also realized practical and
theoretical limitations to using genetic inactivation of individual amacrine cell types to study their roles in retinal
function. Building on past experience, here we propose alternative approaches to studying inhibition:
conditional deletion of postsynaptic inhibitory receptors at specific points in well-studied retinal circuits, and
perturbation of plasmalemmal GABA transporters (GATs).
Our preliminary data demonstrate newly-developed mouse genetic tools for conditional knockout (KO) of
proteins that are required for functional GABAA or glycine receptors (GABAAR, GlyR). Aim 1 will extend these
studies, focusing on gephyrin, which is essential for forming glycinergic synapses, and beta subunits of the
GABAAR, which are essential for forming GABAergic synapses. Subsequent experiments will evaluate the
structural consequences of protein KO in retinal ganglion cells using super-resolution microscopy (STochastic
Optical Reconstruction Microscopy; STORM). We will determine the functional consequences of protein KO on
ganglion cell physiology; these experiments will reveal possible mechanisms for compensation following
inhibitory receptor deletion versus consequences of inhibitory receptor deletion on receptive fields.
Our preliminary data present a completely novel view of GAT-3 function in the mammalian retina. Likely
expressed on Müller glial cells, GAT-3 appears to limit presynaptic inhibition of transmission mediated by
GABABRs. In Aim 2, we propose optogenetic studies of inhibitory synapses that converge onto ON Alpha or
direction-selective ganglion cells. We will test the hypotheses arising from preliminary observations that GAT-3
regulates the strength of synaptic transmission by regulating feedback mechanisms that would otherwise
suppress neurotransmitter release. The functional significance of this regulation will be assessed by studies of
GAT-3-dependent modulation of receptive field properties in ganglion cell circuits.
The proposed studies will advance our understanding of the mechanisms for inhibitory synaptic transmission in
the retina and reveal the role of synaptic inhibition in retinal ganglion cell function. The outcome could inform
therapies for treating retinal dis...

## Key facts

- **NIH application ID:** 10004036
- **Project number:** 5R01EY014454-17
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jonathan B Demb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $413,446
- **Award type:** 5
- **Project period:** 2004-12-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004036

## Citation

> US National Institutes of Health, RePORTER application 10004036, Neural Circuits and Synapses for Early Visual Processing (5R01EY014454-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10004036. Licensed CC0.

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