The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons

Genetic variations in CACNA1C, which encodes the Ca(v)1.2 subunit of L-type calcium channels (LTCCs), are associated with multiple forms of neuropsychiatric disease that manifest high anxiety in patients. In parallel, mice harboring forebrainspecific conditional knockout of cacna1c (forebrain-Ca(v)1.2 cKO) display unusually high anxiety-like behavior. LTCCs in general, including the Ca(v)1.3 subunit, have been shown to mediate differentiation of neural precursor cells (NPCs). However, it has not previously been determined whether Ca(v)1.2 affects postnatal hippocampal neurogenesis in vivo. Here, we show that forebrain-Ca(v)1.2 cKO mice exhibit enhanced cell death of young hippocampal neurons, with no change in NPC proliferation, hippocampal size, dentate gyrus thickness, or corticosterone levels compared with wild-type littermates. These mice also exhibit deficits in brain levels of brain-derived neurotrophic factor (BDNF), and Cre recombinase-mediated knockdown of adult hippocampal Ca(v)1.2 recapitulates the deficit in young hippocampal neurons survival. Treatment of forebrain-Ca(v)1.2 cKO mice with the neuroprotective agent P7C3-A20 restored the net magnitude of postnatal hippocampal neurogenesis to wild-type levels without ameliorating their deficit in BDNF expression. The role of Ca(v)1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C.