Building retinal motion circuit and its relevance in neurodevelopmental disorders

About This Grant

PROJECT SUMMARY / ABSTRACT How do neurons form specific synaptic connections when surrounded by many potential partners? And how is this process impacted by neural developmental disorders? I address these questions in the mouse retina using the direction-selective circuit as a model system. This circuit enables animals to detect the direction of motion in the visual field and underlies the optokinetic reflex, a reflexive eye movement behavior critical for stabilizing images on the retina when the whole visual field moves. The postsynaptic neuron in this circuit, the direction-selective ganglion cell, preferentially responds to motion in one direction and is inhibited when the motion is in the opposite direction. This computation is dependent on its precise wiring with the processes of the presynaptic partner, an inhibitory interneuron called starburst amacrine cell. What makes the direction-selective circuit particularly powerful for dissecting synaptic specificity is that initially, starburst amacrine cell processes and direction-selective ganglion cell dendrites make multiple physical contacts with one another, independent of directional preference. Yet, despite this initial promiscuous connectivity, during a brief developmental window, there is a burst of synaptogenesis exclusively between the appropriate partners. In Aim 1, I will investigate the molecular mechanisms underlying synaptic specificity in the retinal direction-selective circuit. We have previously shown that spontaneous retinal activity is critical for the formation of circuits that mediate direction-selective ganglion cells to preferentially respond to horizontal motion and that this process occurs independently of transcriptional regulation. Here, I will use synapse-specific proteomics to identify activity-dependent, post-transcriptional or post-translational mechanisms that instruct the formation of horizontal direction-selective circuit and drive horizontal optokinetic reflex behavior. Is synaptic specificity in the retinal direction-selective circuit vulnerable to disruptions in neurodevelopmental disorders? While motion processing deficits in these conditions are typically attributed to cortical dysfunction, emerging evidence suggests that retinal circuits may be critically involved. In Aim 2, I will utilize two well-established mouse models of neurodevelopmental disorders to characterize changes in optokinetic reflex and determine whether disruptions in retinal direction-selective circuit contribute to altered motion processing. By linking molecular changes to circuit dysfunction and altered behavior, this work will provide new insight into the developmental logic and disease resilience of synaptic specificity in the retinal direction- selective circuit.