Cav1.2 channels mediate persistent chronic stress-induced behavioral deficits that are associated with prefrontal cortex activation of the p25/Cdk5-glucocorticoid receptor pathway

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. (c) 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.