Upregulation of Rod Ribbon Synapse Components Implies Homeostatic Presynaptic Scaling in Early‐stage Retinitis Pigmentosa

Aims/Purpose: Photoreceptor death triggers retinal rewiring and remodeling that are generally thought to be detrimental for vision. Some recent research results challenge this dogma. It was recently shown that in early‐stage retinitis pigmentosa (RP), the retina compensates for the reduced rod population activity by upscaling synaptic transmission between the remaining rods and rod bipolar cells. The purpose of the current project is to study the molecular mechanism behind this phenomenon.Methods: To model the primary pathology, P23H mouse model of autosomal dominant RP was used. Notably, wild‐type mice were not used as controls, instead, cone‐transducin (GNAT2) knockout mice that lack cone photoreceptor functionality were used. To produce “rod‐function‐only” RP mice, P23H and Gnat2‐/‐ mice were cross‐bred. Single cell RNA‐sequencing (scRNA‐seq; Gnat2‐/‐, n = 4; P23H/Gnat2‐/‐, n = 4) and retinal global proteomics (Gnat2‐/‐, n = 5; P23H/Gnat2‐/‐, n = 10) analyses were performed at P30. Statistical significance was set at q < 0.05. Additional protein expression analyses for synaptic proteins were performed using immunohistochemistry and immunoblotting.Results: ScRNA‐seq analysis revealed upregulation of several major ribbon synapse genes exclusively in P23H/Gnat2‐/‐ mouse rods. These included genes that are crucial in presynaptic structure and neurotransmitter release, such as the Ca2+ sensor Syt1, snare protein complex component Snap25, ribbon protein Ctbp2, and the synaptic vesicle protein Sv2b. In addition, upregulation of the glutamate transporter Slc1a2 was found. Based on proteomics data, STX1B and SYT7 were overexpressed in whole P23H/Gnat2‐/‐ mouse retinas as compared to controls.Conclusions: Early‐stage RP in mice associates with increased expression of several rod ribbon synapse components that play a role in glutamate release. These results imply that regulation of presynaptic glutamate release may play a role in improving retinal synaptic transmission during RP.