Disrupted Cacna1c gene expression perturbs spontaneous Ca2+ activity causing abnormal brain development and increased anxiety

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-02, Vol.119 (7)
• Main Authors: Smedler, Erik, Louhivuori, Lauri, Romanov, Roman A, Masini, Débora, Ellström, Ivar Dehnisch, Wang, Chungliang, Caramia, Martino, West, Zoe, Zhang, Songbai, Rebellato, Paola, Malmersjö, Seth, Brusini, Irene, Kanatani, Shigeaki, Fisone, Gilberto, Harkany, Tibor, Uhlén, Per
• Format: Article
• Language: English
• Subjects: Animals; Anxiety; Anxiety Disorders; Biological Clocks; Biological Sciences; Bipolar disorder; Brain; brain development; Cacna1c; Calcium; Calcium Channels; Calcium channels (L-type); Calcium channels (voltage-gated); Calcium ions; calcium signaling; Cells (biology); Cerebral cortex; Computational neuroscience; Developmental; Embryogenesis; Embryonic growth stage; Gene expression; Gene Expression Regulation; Genetic Predisposition to Disease; genetics; growth & development; Knockout; L-Type; Magnetic resonance imaging; Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy); Medicin och hälsovetenskap; Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Membrane potential; Mental disorders; metabolism; Mice; Molecular machines; Neocortex; Neural networks; Neural Stem Cells; Neurosciences; Neurovetenskaper; Periaqueductal gray area; Progenitor cells; psychiatric disorders; Schizophrenia
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2108768119

The L-type voltage-gated Ca2+ channel gene CACNA1C is a risk gene for various psychiatric conditions, including schizophrenia and bipolar disorder. However, the cellular mechanism by which CACNA1C contributes to psychiatric disorders has not been elucidated. Here, we report that the embryonic deletion of Cacna1c in neurons destined for the cerebral cortex using an Emx1-Cre 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 Cacna1c knockout mouse brains revealed volumetric differences in the neocortex, hippocampus, and periaqueductal gray. These results suggest that Cacna1c 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.