Deletion of psychiatric risk gene Cacna1c impairs hippocampal neurogenesis in cell‐autonomous fashion

Ca2+ is a universal signal transducer which fulfills essential functions in cell development and differentiation. CACNA1C, the gene encoding the alpha‐1C subunit (i.e., Cav1.2) of the voltage‐dependent l‐type calcium channel (LTCC), has been implicated as a risk gene in a variety of neuropsychiatric disorders. To parse the role of Cav1.2 channels located on astrocyte‐like stem cells and their descendants in the development of new granule neurons, we created TgGLAST‐CreERT2/Cacna1cfl/fl/RCE:loxP mice, a transgenic tool that allows cell‐type‐specific inducible deletion of Cacna1c. The EGFP reporter was used to trace the progeny of recombined type‐1 cells. FACS‐sorted Cacna1c‐deficient neural precursor cells from the dentate gyrus showed reduced proliferative activity in neurosphere cultures. Moreover, under differentiation conditions, Cacna1c‐deficient NPCs gave rise to fewer neurons and more astroglia. Similarly, under basal conditions in vivo, Cacna1c gene deletion in type‐1 cells decreased type‐1 cell proliferation and reduced the neuronal fate‐choice decision of newly born cells, resulting in reduced net hippocampal neurogenesis. Unexpectedly, electroconvulsive seizures completely compensated for the proliferation deficit of Cacna1c deficient type‐1 cells, indicating that there must be Cav1.2‐independent mechanisms of controlling proliferation related to excitation. In the aggregate, this is the first report demonstrating the presence of functional L‐type 1.2 channels on type‐1 cells. Cav1.2 channels promote type‐1 cell proliferation and push the glia‐to‐neuron ratio in the direction of a neuronal fate choice and subsequent neuronal differentiation. Cav1.2 channels expressed on NPCs and their progeny possess the ability to shape neurogenesis in a cell‐autonomous fashion. Main Points This report demonstrates the functional presence of CaV1.2‐channels on type‐1 cells of the dentate gyrus. Our work establishes that CaV1.2 channels expressed on NPCs and their progeny shape adult neurogenesis in a cell‐autonomous fashion.