期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2108768119
关键词
Cacna1c; calcium signaling; brain development; psychiatric disorders; anxiety
资金
- Swedish Research Council [2013-3189, 2017-00815, 2021-03108]
- Swedish Brain Foundation [FO2017-0107, FO2018-0209, FO2020-0199]
- Swedish Cancer Society [CAN 2016-801, 19 0545]
- Swedish Childhood Cancer Foundation [PR2018-0123, PR2020-0124]
- Linnaeus Centre in Developmental Biology for Regenerative Medicine
- Knut and Alice Wallenberg Foundation
- Karolinska Institutet's KID doc-toral program
- European Molecular Biol-ogy Organization advanced research fellow [ALTF 596-2014]
- European Commission FP7 (Marie Curie Actions, EMBOCO-FUND2012) [GA-2012-600394]
This study demonstrates that embryonic deletion of CACNA1C in neurons destined for the cerebral cortex disrupts Ca2+ activity, leading to abnormal brain development and anxiety.
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.
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