Molecular Basis of Photoreceptor Wiring

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PROJECT SUMMARY Mammalian rod and cone photoreceptors are indispensible for vision. They convert light into electrical response, which is then propagated across the retina circuit and into the brain. Transmission of the electrical signal generated by the photoreceptors requires their synaptic connectivity with the downstream interneurons, the bipolar cells. Deficits in synaptic communication between photoreceptors and bipolar cells are known to cause congenital stationary blindness in humans, a condition characterized by poor light sensitivity and frequent co-morbidity with many other ocular conditions. Our long-term goal is to elucidate molecular and cellular mechanisms by which photoreceptors establish synapses and transmit their signals with the hope to better understand blinding conditions and devising strategies for their treatment. Two types of the photoreceptors, rods and cones, form distinct connections with different types of the bipolar cells. This synaptic specificity segregates visual inputs and plays an essential role in setting up the fundamental properties of our vision, including a wide dynamic range of light sensitivity and contrast discrimination. However, the molecular mechanisms responsible for selective connectivity between photoreceptors and their downstream bipolar neurons are unknown. We have identified a new cell adhesion- like molecule ELFN1 that specifically present at the photoreceptors synapses. We found that ELFN1 forms a trans-synaptic interaction with the principal neurotransmitter receptor in bipolar cells, mGluR6. Disruption of ELFN1 results in selective loss of rod synapses. We hypothesize that ELFN1-mGluR6 interaction play key roles in mediating selective synaptic connectivity of rod photoreceptors and direct the propagation of light signal across retina circuit. This hypothesis will be tested by pursuing three complementary Specific Aims that will (i) use knockout mouse models, and genetic rescue experiments to determine cellular mechanisms of ELFN1 function in the formation of synapse between rod photoreceptors and ON-RBC, (ii) investigate the role of ELFN1 in directing the propagation light signal across retina circuitry, and (iii) examine molecular mechanisms by which ELFN1 enables its synaptogenic effects. The strategy proposed to address these aims will entail a synergistic combination of biochemical, molecular biological, electrophysiological, and physiological approaches, each exploiting the existence of a powerful array of reagents and animal models.