Synaptic Mechanisms in the Mammalian Retina

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Our work focuses on specialized synapses in the inner retina. Recent transcriptomic analyses of retinal neurons have generated many interesting hypotheses that we plan to test. For example, GluA1, an AMPA receptor subunit that is expressed widely throughout the rest of the brain, exhibits markedly restricted expression in the retina. In the inner retina, GluA1 is expressed primarily in a single amacrine cell and a single retinal ganglion cell (RGC), and we have planned electrophysiological, imaging and immunohistochemical experiments to determine specific roles for that receptor in visual processing within these neurons. 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 are performing electrophysiological and Ca2+ imaging experiments to examine the properties of these synapses, which we hypothesize exert extremely powerful inhibitory control over the spiking activity of OFF alpha ganglion cells. 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. Answers to this question would suggest specific pharmacological approaches to preserve signaling and alleviate damaging circuit remodeling during the onset of the disease. Many neuroscience laboratories, including ours (Poleg-Polsky and Diamond, 2016, J. Neurosci), have used iGluSnFR, a genetically encoded glutamate indicator, to study various aspects of circuit features. Recently, we used computational, electrophysiological and imaging methods to examine the effects that iGluSnFR has on glutamate diffusion and uptake (Armbruster, et al., 2020, eLife). We find that iGluSnFR substantially delays glutamate uptake, as indicated by a slowing of synaptic transporter currents. These results highlight important considerations and caveats when using this valuable tool.