Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C subunit of the voltage-gated L-type calcium channel Ca_v1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Ca_v1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene × environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Ca_v1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Ca_v1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.

中文翻译：

---

跨疾病风险基因 CACNA1C 差异调节发育和成年期间对精神疾病的易感性。

_{CACNA1C（电压门控 L 型钙通道 Ca v} 1.2的 α1C 亚基）中的单核苷酸多态性 (SNP) 属于精神病学中最一致和可复制的遗传学发现之一，与精神分裂症、双相情感障碍和重度抑郁症相关。然而，复杂疾病的遗传变异通常只会略微增加疾病风险，而且还受到环境的影响。在这里，我们发现前脑谷氨酸能神经元中 Cacna1c 的胚胎缺失会促进与精神疾病相关的内表型的表现，包括认知能力下降、突触可塑性受损、社交能力降低、多动和焦虑增加。其他分析显示，胚胎发育过程中 Cacna1c 的消耗也会增加对慢性应激的易感性，这表明 Ca _v 1.2 与环境相互作用，从而影响疾病的易感性。值得注意的是，当成年期谷氨酸能神经元中的 Cacna1c 被删除时，并没有观察到这一点，后来的删除甚至提高了认知灵活性，增强了突触可塑性并诱导了应激恢复能力。在人类的平行基因×环境设计中，我们还证明 CACNA1C 中的 SNP 与不良生活事件显着相互作用，以改变出现精神疾病症状的风险。总体而言，我们的结果进一步验证了 Cacna1c 作为小鼠和人类的跨疾病风险基因，并且还表明 Ca _v 1.2 在发育和成年期在塑造认知、社交能力、情绪行为和压力敏感性方面发挥着不同的作用。这可能会促使人们考虑对 Ca _v 1.2 进行药理学操作，以治疗具有发育和/或应激相关起源的神经精神疾病。