Friday, April 4, 2025
4/4/2025
Molecular Basis of Photoreceptor Wiring - PROJECT SUMMARY Mammalian rod and cone photoreceptors are indispensible for vision. They convert light into an electrical responses, which are then propagated across the retinal circuitry and into the brain. Fundamental to this information transmission is the specificity of synaptic connections between rod and cone photoreceptors and their downstream partners, the bipolar cells. Deficits in synaptic transmission between photoreceptors and bipolar cells are known to cause congenital stationary blindness in humans, a condition characterized by poor light sensitivity and is a frequent co-morbidity with many other ocular conditions. Our long term goal is to elucidate the molecular and cellular mechanisms by which photoreceptors establish synapses with bipolar cells. We believe that a better understand of the mechanisms underlying blinding conditions will ultimately help in devising strategies for their treatment. In this renewal application, we will continue our highly productive Multi-PI team effort that thus far has led to major advances in understanding photoreceptor synaptic biology, We now turn our attention to a radically new set of trans-synaptic adhesion molecules at cone synapses. Specifically, we will focus on the molecules LRIT1 and adhesion GPCR – LPHN3, which our preliminary data show operate at cone synapses. Through cell biological, biochemical, electrophysiological (single cell and whole retina), and behavioral experiments we will elucidate the mechanism of action LRIT1 and LPHN3, which will reveal key properties of these synapses that support vision over a wide range of light intensities. We hypothesize that LRIT1 and LPHN3 are critically involved in shaping the function of CaV1.4 calcium channels that mediate neurotransmitter from photoreceptor terminals through mechanisms that in part that involve inhibitory feedback between cones through horizontal cells. We will test this hypothesis by pursuing two complementary Specific Aims that will (i) investigate mechanistic role of LRIT1 in controlling the cone photoreceptor output, and (ii) elucidate the molecular basis of LPHN3 effects from horizontal cells in regulating calcium channel activity at cone photoreceptor terminals.
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