L-type Ca2+ channels in mouse rod bipolar cells

L-type calcium channels (LTCC) are key molecular components controlling many physiological processes. In the mouse and human retina CaV1.4 LTCCs are the most prominently expressed mediating synaptic vesicle release. Many mutations in the CACNA1F gene, which encodes for Cav1.4 LTCC a1 subunits, have been shown to cause X-linked visual disorders in humans including incomplete Congenital Stationary Night Blindness. Importantly, expression of CaV1.4 was reported in photoreceptors as well as bipolar cells of the mouse retina. Bipolar cells initiate the partitioning of visual information into parallel pathways that ultimately lead to the retinal extraction of visual features which get transmitted to higher visual brain regions. Existing models of CaV1.4 perturbation, however, allow mainly for the study of photoreceptor phenotypes. Effects of CaV1.4 mutations on synaptic transmission from bipolar cells cant be investigated because outer retinal function is already disturbed and bipolar cells exert remodelling strategies. The aim of this project is to gain a better insight into the specific function of the CaV1.4 LTCCs on selected retinal cells physiology and synaptic output. To this end, we will target rod bipolar cells for genetic manipulation to allow for investigation of the morphological and physiological impact of cell- specific perturbations. The novelty in this approach is the exclusion of an involvement of photoreceptors, allowing for greater mechanistic insight at the second order neuron level, also linking CaV1.4 to specific retinal functions. Importantly in advanced stages of degenerative diseases, often in the absence of photoreceptors, stimulation of inner retinal neurons in particular rod bipolar cells are feasible approaches in the restoration of vision in blind patients. Thus, deeper understanding on the role of Cav1.4 LTCCs for bipolar cell function and their contribution to human retinal pathophysiology is essential, also in the light of potential future therapeutic approaches.