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Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders
Dibyadeep Datta1,2, Shengtao Yang1, Mary Kate P Joyce1
1Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut.
JAMA Psychiatry
|May 22, 2024
Summary
Variants in CACNA1C channels impact mental health by affecting specific neurons in the brain. This study reveals how L-type calcium channels (Cav1.2) in dorsolateral prefrontal cortex layer III pyramidal cells influence cognitive function and risk for disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Genetic variants in CACNA1C (L-type calcium channel Cav1.2) are linked to mental disorders.
- The specific role of these channels in cognitive function, particularly in dorsolateral prefrontal cortex (dlPFC) layer III pyramidal cells, remains unclear.
- These dlPFC neurons are particularly vulnerable in cognitive disorders.
Purpose of the Study:
- To investigate the molecular mechanisms within layer III pyramidal cells of primate dlPFC.
- To understand how CACNA1C variants contribute to cognitive deficits.
Main Methods:
- Transcriptomic analysis of human and macaque dlPFC.
- Assessing protein expression, neuronal connectivity, and physiology in macaques.
- Evaluating cognitive behavior and working memory performance following pharmacological interventions.
Main Results:
- Layer III pyramidal cells coexpress calbindin (CALB1), CACNA1C (Cav1.2), GRIN2B (GluN2B), and KCNN3 (SK3).
- L-type calcium channels critically influence neuronal firing for working memory.
- Pharmacological blockade or enhancement of Cav1.2 channels, or modulation via β1-adrenoceptors and SK channels, altered neuronal firing and working memory performance.
- L-type calcium channel blockers or β1-adrenoceptor antagonists protected working memory against stress.
Conclusions:
- Layer III pyramidal cells in the dlPFC, vulnerable in cognitive disorders, express a unique set of calcium-related proteins including Cav1.2, GluN2B, and SK3 channels.
- Dysregulation of L-type calcium channel activity (both insufficient and excessive) impairs neuronal firing, explaining CACNA1C variant-associated cognitive disorder risks.
- Calbindin expression in these neurons highlights critical calcium signaling regulation, relevant to age-related cognitive decline and Alzheimer's pathology.
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