The long-term goal of our research is to understand how the properties of Cav channels shape their neural functions. The objective of this competing renewal application is to define the Cav1-dependent signaling pathways that shape the development and plasticity of the photoreceptor (PR) synapse. Among the major Cav1 subtypes expressed in the retina, Cav1.4 is uniquely critical for PR synaptogenesis. How Cav1.4 contributes to this process remains a mystery—a major challenge being that available animal models do not distinguish between the roles of Cav1.4 as a source of Ca2+ ions and as a scaffold for synaptogenic proteins. To overcome this hurdle, we generated a knock-in mouse strain expressing a non-conducting mutant form of Cav1.4. While the molecular organization of PR synapses is largely spared in these mice, the maturation of synaptic ribbons and invagination of postsynaptic neurites into PR terminals is disrupted. Our findings raise the intriguing possibility that the clinical variability associated with CSNB2 could arise from heterogeneous impacts of the mutations on the organization, development, and mature function of the PR synapse. Our central hypothesis is that Cav1.4 mediates Ca2+ signaling pathways that promote the maturation of synaptic ribbons and the postsynaptic architecture of PR synapses via mechanisms that are disrupted in CSNB2. We will test this hypothesis with the following Aims: (1) Elucidate the mechanism whereby Cav1.4 Ca2+ signals regulate the maturation and plasticity of synaptic ribbons (2) Define the role of Cav1 Ca2+ signals in enabling the postsynaptic wiring of PR synapses (3) Determine the impact of pathological variants of human Cav1.4 channels on PR synapse structure and function. The overall impact of our research will be knowledge of: (a) the multi-faceted roles of Cav channels at a synapse that is crucial for vision, and (b) how dysregulation specifically of Cav1.4 could lead to heterogeneous forms of vision impairment. More broadly, our research is expected to provide insights into mechanisms that enable the proper synaptic connectivity in the retina—a requirement for the successful restoration of vision through cell transplantation therapies.

In this proposal we will investigate the roles for synaptic calcium channels in the organization and function of the photoreceptor synapse. Results of this work will promote the development of new approaches to treat injuries and diseases of the retina that cause blindness by disrupting synaptic communication.