PROJECT SUMMARY/ABSTRACT The retina is comprised of neural circuit ensembles that communicate through connections called synapses to generate visual perception and behavior. Retinal diseases cause signaling deficits that derail this communication and block information flow traveling from the retina to the brain. Severe congenital stationary night blindness is of particular interest because despite complete suppression of signal transmission through the on retinal pathway that signals light increments, the on neural circuitry is anatomically intact. Alpha ganglion cells, the primary output neurons of retinal pathways that code for specific visual features, receive excitatory and inhibitory synaptic inputs, integrate these inputs across their dendritic compartments, and generate and transmit trains of action potentials to the brain. We know that neural circuits can adopt diverse strategies to conduct precise synaptic computations and generate response properties, however, the cellular and synaptic factors prone to alteration during retinal diseases are not well understood. This proposal seeks to address important unanswered questions about the mechanisms of neural compensation that occur in response to specific signaling deficits in well-defined alpha retinal output circuits. Using a set of neurophysiological and anatomical approaches, these experiments will define how intrinsic properties and synaptic computations of alpha retinal ganglion cells are altered when the synaptic inputs and balance of excitation/inhibition that a neuron receives is perturbed. Two CRISPR-edited knockout models of the principal glutamate receptor of the on retinal pathway, mGluR6, will be used to study neural compensation in the inner retina across homozygous (100% block) and heterozygous (50% block) conditions. We will correlate single cell electrophysiology with high resolution imaging and visual behavior assays to complement observations across the cellular, synaptic, and behavioral levels. Together, the proposed experiments stand to significantly deepen our mechanistic understanding of the substrates of neural compensation in the inner retina and define the cellular and synaptic deficits of severe congenital stationary night blindness.