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

Anni S. Lee, Héctor De Jesús-Cortés, Zeeba D. Kabir, Whitney Knobbe, Madeline Orr, Caitlin Burgdorf, Paula Huntington, Latisha McDaniel, Jeremiah K. Britt, Franz Hoffmann, Daniel J. Brat, Anjali M. Rajadhyaksha*, Andrew A. Pieper

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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 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 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. Visual Abstract.

Original languageEnglish (US)
Pages (from-to)3576-3581
Number of pages6
JournaleNeuro
Volume3
Issue number2
DOIs
StatePublished - Mar 1 2016

Keywords

  • anxiety
  • Cav
  • neurogenesis
  • neuroprotection
  • P7C3
  • P7C3A20

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons'. Together they form a unique fingerprint.

Cite this