Bavley Charlotte C, Fischer Delaney K, Rizzo Bryant K, Rajadhyaksha Anjali M
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA.
Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA.
Neurobiol Stress. 2017 Feb 24;7:27-37. doi: 10.1016/j.ynstr.2017.02.004. eCollection 2017 Dec.
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 , which codes for the Ca1.2 subunit of the L-type calcium channel (LTCC), as a common risk variant for multiple neuropsychiatric conditions. Ca1.2 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 Ca1.2 expression in the brain, however the contribution of Ca1.2 channels to chronic stress-induced behaviors, and the precise Ca1.2 signaling mechanisms activated are currently unknown. Here we report that chronic stress leads to a delayed increase in Ca1.2 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 Ca1.2 heterozygous (Ca1.2) 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 Ca1.2 mice. Our findings reveal a novel Ca1.2-mediated molecular mechanism associated with the persistent behavioral effects of chronic stress and provide new insight into potential Ca1.2 channel mechanisms that may contribute to linked neuropsychiatric phenotypes.
已知慢性应激会引发并加剧神经精神症状，对于具有某些遗传易感性的个体而言，暴露于应激环境尤其具有病理性。最近的全基因组关联研究已确定基因中的单核苷酸多态性（SNP）是多种神经精神疾病的常见风险变异，该基因编码L型钙通道（LTCC）的Ca1.2亚基。Ca1.2通道通过激活下游钙信号通路介导基因表达中依赖经验的变化以及长期突触可塑性。先前的研究发现应激与大脑中Ca1.2表达的改变之间存在关联，然而，Ca1.2通道对慢性应激诱导行为的作用以及所激活的精确Ca1.2信号传导机制目前尚不清楚。在此我们报告，慢性应激导致前额叶皮质（PFC）内Ca1.2表达选择性延迟增加，但在海马体或杏仁核等其他应激敏感脑区则不然。此外，我们证明，虽然Ca1.2杂合（Ca1.2）小鼠在应激后1 - 2天表现出慢性应激诱导的抑郁样行为、焦虑样行为和工作记忆缺陷，但在5 - 7天后测试时，它们对慢性应激的影响具有抵抗力。最后，分子研究发现，在应激后8天检查时，PFC中p25/Cdk5 - 糖皮质激素受体（GR）通路存在延迟上调，而在Ca1.2小鼠中则不存在。我们的研究结果揭示了一种与慢性应激的持续行为影响相关的新型Ca1.2介导的分子机制，并为可能导致相关神经精神表型的潜在Ca1.2通道机制提供了新的见解。
