Function of cone and cone-related pathways in Ca_V1.4 IT mice

Ca_V1.4 L-type calcium channels are predominantly expressed in photoreceptor terminals playing a crucial role for synaptic transmission and, consequently, for vision. Human mutations in the encoding gene are associated with congenital stationary night blindness type-2. Besides rod-driven scotopic vision also cone-driven photopic responses are severely affected in patients. The present study therefore examined functional and morphological changes in cones and cone-related pathways in mice carrying the Ca_V1.4 gain-of function mutation I756T (Ca_V1.4-IT) using multielectrode array, patch-clamp and immunohistochemical analyses. Ca_V1.4-IT ganglion cell responses to photopic stimuli were seen only in a small fraction of cells indicative of a major impairment in the cone pathway. Though cone photoreceptors underwent morphological rearrangements, they retained their ability to release glutamate. Our functional data suggested a postsynaptic cone bipolar cell defect, supported by the fact that the majority of cone bipolar cells showed sprouting, while horizontal cells maintained contacts with cones and cone-to-horizontal cell input was preserved. Furthermore a reduction of basal Ca²⁺ influx by a calcium channel blocker was not sufficient to rescue synaptic transmission deficits caused by the Ca_V1.4-IT mutation. Long term treatments with low-dose Ca²⁺ channel blockers might however be beneficial reducing Ca²⁺ toxicity without major effects on ganglion cells responses.