Disrupted <i>Cacna1c</i> gene expression perturbs spontaneous Ca²⁺ activity causing abnormal brain development and increased anxiety.

Abstract

The L-type voltage-gated Ca²⁺ channel gene <i>CACNA1C</i> is a risk gene for various psychiatric conditions, including schizophrenia and bipolar disorder. However, the cellular mechanism by which <i>CACNA1C</i> contributes to psychiatric disorders has not been elucidated. Here, we report that the embryonic deletion of <i>Cacna1c</i> in neurons destined for the cerebral cortex using an <i>Emx1-Cre</i> strategy disturbs spontaneous Ca²⁺ activity and causes abnormal brain development and anxiety. By combining computational modeling with electrophysiological membrane potential manipulation, we found that neural network activity was driven by intrinsic spontaneous Ca²⁺ activity in distinct progenitor cells expressing marginally increased levels of voltage-gated Ca²⁺ channels. MRI examination of the <i>Cacna1c</i> knockout mouse brains revealed volumetric differences in the neocortex, hippocampus, and periaqueductal gray. These results suggest that <i>Cacna1c</i> acts as a molecular switch and that its disruption during embryogenesis can perturb Ca²⁺ handling and neural development, which may increase susceptibility to psychiatric disease.