Synaptic Mechanisms in the Mammalian Retina

National Institute Of Neurological Disorders And Stroke

Investigators

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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 (some discussion of this appears in the published review). 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 results indicate that -3-expressing RGCs exhibit distinct AMPA receptor kinetics compared to the same RGCs in -3 knockout mice. These differences are also apparent in light-evoked responses. 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 experiments now indicate that this hypothesis is wrong a range of release probabilities exists among the docked vesicles at these synapses. Other experiments suggest that this heterogeneity may work together with the voltage-dependence of presynaptic Cav channels to enable this synapse to work over a wider dynamic range. 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 have confirmed aspects of these results in in vitro electroretinograms (ERGs) and are currently performing recordings from Rod bipolar cells prior to writing a manuscript.