Synaptic Mechanisms in the Mammalian Retina

National Institute Of Neurological Disorders And Stroke

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Abstract

Our work focuses on specialized synapses in the inner retina. The mouse retina contains 46 different ganglion cells (RGCs), but very little is known regarding the diversity of excitatory synapses across these cell types. Recent transcriptomic analyses suggest that different RGC types express distinct sets of glutamate receptor subunits, but the physiological implications of these patterns are unknown. For example, GluA1, an AMPA receptor subunit, expressed widely throughout the rest of the brain, appears primarily in a single RGC type. Similarly, only a limited subset of RGCs express the AMPA receptor modulatory protein -3. Our initial experiments indicate that -3-expressing RGCs exhibit distinct AMPA receptor kinetics compared to similar RGCs that do not express -3. We have obtained a -3-knockout mouse to explore the physiological role for this auxiliary synaptic protein in visual signaling. Current work in the lab has identified previously unreported synapses in the rod pathway. Specifically, A2 amacrine cells make synapses directly onto the proximal dendrites, somata and axons of OFF alpha ganglion cells. We have performed electron microscopy, electrophysiological and Ca2+ imaging experiments to examine the properties of these synapses, which exert powerful inhibitory control over the visual responsivity of OFF alpha ganglion cells. A manuscript has been reviewed at Current Biology, and a revision has been invited. The role of synaptic ribbons in retinal synapses remains enigmatic. We hypothesize that these distinct presynaptic structures optimize analog signaling by ensuring a consistent relationship between presynaptic calcium channels and vesicle release sites. Our preliminary data indicates that each vesicle release site within a single release site exhibits a similar release probability, and synaptic simulations argue that this enhances the ability of these synapses to compute visual contrast over a wider response range. Ongoing experiments are directed towards determining the vesicle release probability under different conditions and the biophysical mechanisms that influence this critical parameter in rod bipolar cell terminals. Our studies of pathological activity in the rd10 mouse model of retinitis pigmentosa have given rise to several hypotheses regarding synaptic features that are altered during this process and potential therapies to alleviate synaptic and circuit dysfunction. Specifically, we are testing whether pathological depolarization of RBCs diminishes signaling in the rod pathway. Recording from retinal ganglion cells, we have found that reducing RBC depolarization can reduce pathological oscillatory behavior with minimal impact on visual signaling. We are confirming these results in in vitro electroretinograms (ERGs) and, following control experiments requiring RBC recordings, will draft a manuscript.