Ca v 1.2 channels mediate persistent chronic stress-induced behavioral deficits that are associated with prefrontal cortex activation of the p25/Cdk5-glucocorticoid receptor pathway
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Chronic stress is known to precipitate and exacerbate neuropsychiatric symptoms, and exposure to stress is particularly pathological in individuals with certain genetic predispositions. Recent genome wide association studies have identified single nucleotide polymorphisms (SNPs) in the gene CACNA1C , which codes for the Ca v 1.2 subunit of the L-type calcium channel (LTCC), as a common risk variant for multiple neuropsychiatric conditions. Ca v 1.2 channels mediate experience-dependent changes in gene expression and long-term synaptic plasticity through activation of downstream calcium signaling pathways. Previous studies have found an association between stress and altered Ca v 1.2 expression in the brain, however the contribution of Ca v 1.2 channels to chronic stress-induced behaviors, and the precise Ca v 1.2 signaling mechanisms activated are currently unknown. Here we report that chronic stress leads to a delayed increase in Ca v 1.2 expression selectively within the prefrontal cortex (PFC), but not in other stress-sensitive brain regions such as the hippocampus or amygdala. Further, we demonstrate that while Ca v 1.2 heterozygous (Ca v 1.2 +/− ) mice show chronic stress-induced depressive-like behavior, anxiety-like behavior, and deficits in working memory 1–2 days following stress, they are resilient to the effects of chronic stress when tested 5–7 days later. Lastly, molecular studies find a delayed upregulation of the p25/Cdk5-glucocorticoid receptor (GR) pathway in the PFC when examined 8 days post-stress that is absent in Ca v 1.2 +/− mice. Our findings reveal a novel Ca v 1.2-mediated molecular mechanism associated with the persistent behavioral effects of chronic stress and provide new insight into potential Ca v 1.2 channel mechanisms that may contribute to CACNA1C- linked neuropsychiatric phenotypes.
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More severe, longer-lasting stress procedures produce anxiety- and depression-like phenotypes in these tasks.
“This contrasts with more severe, longer-lasting stress procedures, which do produce anxiety- and depression-like phenotypes in these tasks80,100,101.”
From A dual-pathway architecture for stress to disrupt agency and promote habit (2025) · cites this paper as [80]
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- Authors
- Bavley, C. C., Fischer, D. K., Rizzo, B. K., & Rajadhyaksha, A. M.
- Affiliations
- Cornell University (US)
- Corresponding author
- Rajadhyaksha, Anjali M.
- Venue
- Neurobiology of Stress
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 7
- Pages
- 27-37
- ISSN
- 2352-2895 (ISSN-L)
- PMC
- PMC5338724
- OpenAlex
- W2589603677
- Cited by
- 41
- References
- 79
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 9 · 2019: 6 · 2018: 3 · 2017: 6
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neurobiology of Stress (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Hartwell Foundation
- Weill Cornell Medical College
- National Institute on Drug Abuse (R01DA029122, T32DA039080)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- L-type calcium channels, CACNA1C, chronic stress, prefrontal cortex, glucocorticoid receptor, depression-like behavior, anxiety-like behavior, working memory deficits, stress resilience, neuropsychiatric disorders, single nucleotide polymorphisms
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