The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons123

Genetic variations in CACNA1C, which encodes the Cav1.2 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 forebrain-specific conditional knockout of cacna1c (forebrain-Cav1.2 cKO) display unusually high anxiety-like behavior. LTCCs in general, including the Cav1.3 subunit, have been shown to mediate differentiation of neural precursor cells (NPCs). However, it has not previously been determined whether Cav1.2 affects postnatal hippocampal neurogenesis in vivo. Here, we show that forebrain-Cav1.2 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 to wild type littermates. These mice also exhibit deficits in brain levels of brain-derived neurotrophic factor (BDNF), and Cre recombinasemediated knockdown of adult hippocampal Cav1.2 recapitulates the deficit in young hippocampal neurons survival. Treatment of forebrain-Cav1.2 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 Cav1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C. SIGNIFICANCE STATEMENT Aberrant postnatal hippocampal neurogenesis and CACNA1C mutations are associated with neuropsychiatric diseases manifesting high anxiety, and mice deficient in Cav1.2 neuronal expression display high anxiety-like behavior. Here, we report that these mice also display deficient postnatal hippocampal neurogenesis by virtue of elevated death of young hippocampal neurons, along with decreased expression of the endogenous pro-neurogenic agent brain-derived neurotrophic factor (BDNF). We further show that treatment of these mice with the neuroprotective agent P7C3-A20 circumvents the BDNF deficiency to safely and effectively normalize hippocampal neurogenesis without altering BDNF levels. Pharmacologic agents derived from the P7C3 family of neuroprotective compounds could thus provide a new therapeutic approach for treating patients suffering from neuropsychiatric disease associated with aberrations in CACNA1C.