A rare schizophrenia risk variant of CACNA1I disrupts Ca_V3.3 channel activity

CACNA1I is a candidate schizophrenia risk gene. It encodes the pore-forming human Ca_V3.3 α1 subunit, a subtype of voltage-gated calcium channel that contributes to T-type currents. Recently, two de novo missense variations, T797M and R1346H, of hCa_V3.3 were identified in individuals with schizophrenia. Here we show that R1346H, but not T797M, is associated with lower hCa_V3.3 protein levels, reduced glycosylation, and lower membrane surface levels of hCa_V3.3 when expressed in human cell lines compared to wild-type. Consistent with our biochemical analyses, whole-cell hCa_V3.3 currents in cells expressing the R1346H variant were ~50% of those in cells expressing WT hCa_V3.3, and neither R1346H nor T797M altered channel biophysical properties. Employing the NEURON simulation environment, we found that reducing hCa_V3.3 current densities by 22% or more eliminates rebound bursting in model thalamic reticular nucleus (TRN) neurons. Our analyses suggest that a single copy of Chr22: 39665939G > A CACNA1I has the capacity to disrupt Ca_V3.3 channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology.