Sincox, Brittany; (2022) A Closer Look: Investigating the role of synaptic diversity in function of retinal neurons. Masters thesis (M.Phil), UCL (University College London).

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Abstract

Retinal ganglion cells (RGCs), the final step in the retinal circuit, relay visual information to the brain. In mouse retina there are 46 genetically distinct RGC types, with each type encoding a distinct aspect of the visual world. While contributions from electron microscopy and single cell transcriptomics have greatly improved our knowledge of RGC type diversity, the physiological function and visual processing significance of many of these cells is yet to be determined. Morphological, molecular, and physiological diversity have been at the forefront of determining cell-type categorization. However, the diversity of excitatory synapses across cell types has not been explored in the same degree of detail. Visual signal propagating through the retina has a relatively slow time course – significantly slower than the time course of excitatory transmission associated with activation of AMPARs or NMDARs. This could imply little functional necessity for varying AMPAR subunit composition between retinal cell classes -- perhaps explaining why diversity of synaptic receptors has been studied less extensively by retinal neurobiologists. Recent single cell transcriptomics has identified mRNA variation in both AMPAR subunits and their auxiliary proteins across RGCs. Elsewhere in the CNS, diversity in AMPAR composition has been widely studied and the regulation of AMPAR composition has been shown to be important in processes including normal fast transmission, plasticity, neurological disorders and excitotoxicity. Much remains to discover about AMPARs and their modulatory proteins in retinal physiology. In this study, we have focused on the auxiliary AMPAR subunit γ-3 in four α-ganglion cell types. Previous studies show a preferential expression of γ-3 in ON-S-α RGCs, but not OFF-S-α RGCs, making it an ideal target for better understanding the impact of TARPs in the retina. We have examined their post-synaptic currents and light responses in wild type mice and transgenic animals lacking γ-3. ON-S-α RGCs, but not OFF-S-α RGCs, show differences in AMPAR kinetics in γ-3 KO mice. γ-3 markedly slows AMPAR kinetics, causing a delay in the time to the initial spike in response to light stimuli, demonstrating potentially significant functional implications for AMPAR diversity in RGCs. Through quantifying the post-synaptic AMPAR currents in different RGC types, we aimed to reveal another piece of the visual processing puzzle and gain greater understanding of the role of AMPARs in generating light responses.

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