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Neuropeptide releasing amacrine cells modulate microcircuits in the inner retina


Amacrine cells form the most diverse group of interneurons in the retina. There are at least 30 identified types, which are differentiated based on their stratification patterns, neurotransmitter content, and soma and dendritic field sizes. Despite knowing the morphology of each amacrine cell type, our understanding of the connectivity, intrinsic, and functional properties of a majority of the amacrine cell types remain unclear. This study aims to investigate the intrinsic properties of neuropeptide-expressing amacrine cells, as well as their role in modulating inner retinal microcircuits. These studies will focus on two neuropeptide-expressing amacrine cells examined are the somatostatin-expressing (SRIF) and vasoactive intestinal polypeptide-expressing (VIP) amacrine cells.

Previous studies have shown SRIF and VIP amacrine cells play a role in regulating dopamine levels or modulating GABA signaling in the inner retina. In this study we tested how SRIF amacrine cells can modulate the cells that comprise the light adaptation network: dopamine-expressing (DA) amacrine cells and melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). In addition, we used a novel transgenic mouse line to map the intrinsic electrophysiological properties and synaptic partners of VIP amacrine cells.

In order to address these questions about SRIF- and VIP-amacrine cells in the network of cells in the inner retina, I employed a combination of anatomical, pharmacological, and electrophysiological manipulations in multiple transgenic mouse lines. The 3D modeling generated from antibody-labeled whole mount retinas showed the relationship of the processes of SRIF- and DA-amacrine cells, as well as the processes between SRIF amacrine cells and melanopsin ipRGCs. Using pharmacology and whole patch clamp protocols I showed SRIF, acting through specific SRIF receptor subtypes (sst2A and sst4), effectively increases K+ currents, decreases Ca2+ currents, as well as regulate the spontaneous firing rate of both cell types. In addition, SRIF can directly inhibit the intrinsic light response of melanopsin ipRGCs.

Using the VIP-tdTomato transgenic mouse line we detail the ion channel composition of VIP- amacrine cells, which include delayed inward rectifying K+ channels, verapamil-sensitive L-type Ca2+ channels, a hyperpolarizing activated K= channel (Ih), and TTX-sensitive Na+ channel currents. The recorded VIP amacrine cells showed varying combination of these ion channels, suggesting there may be multiple subtypes of VIP amacrine cells. Finally, using a puff protocol, we showed VIP amacrine cells receive inhibitory inputs mediated by GABA and glycine. In addition, they receive excitatory input from type 2 OFF- and type 6 ON-cone bipolar cells, likely through activation of an ionotropic glutamate receptor subtype, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.

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