Kabir Zeeba D, Martínez-Rivera Arlene, Rajadhyaksha Anjali M
Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA.
Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA.
Neurotherapeutics. 2017 Jul;14(3):588-613. doi: 10.1007/s13311-017-0532-0.
The L-type calcium channels (LTCCs) Ca1.2 and Ca1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. Separately, CACNA1D has been found to be associated with BD and autism spectrum disorder, as well as cocaine dependence, a comorbid feature associated with psychiatric disorders. Despite growing evidence of a significant link between CACNA1C and CACNA1D and psychiatric disorders, our understanding of the biological mechanisms by which these LTCCs mediate neuropsychiatric-associated endophenotypes, many of which are shared across the different disorders, remains rudimentary. Clinical studies with LTCC blockers testing their efficacy to alleviate symptoms associated with BD, SCZ, and drug dependence have provided mixed results, underscoring the importance of further exploring the neurobiological consequences of dysregulated Ca1.2 and Ca1.3. Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Ca1.2- and Ca1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.
L型钙通道（LTCCs）Ca1.2和Ca1.3分别由CACNA1C和CACNA1D基因编码，是细胞钙内流的重要调节因子，对正常脑发育和可塑性至关重要。在人类中，CACNA1C已成为一系列神经精神疾病最广泛复制且突出的候选风险基因之一，这些疾病包括双相情感障碍（BD）、精神分裂症（SCZ）、重度抑郁症、自闭症谱系障碍和注意力缺陷多动障碍。另外，已发现CACNA1D与BD、自闭症谱系障碍以及可卡因依赖有关，可卡因依赖是一种与精神疾病相关的共病特征。尽管越来越多的证据表明CACNA1C和CACNA1D与精神疾病之间存在显著联系，但我们对这些L型钙通道介导神经精神相关内表型的生物学机制的理解仍很初步，其中许多内表型在不同疾病中是共有的。使用LTCC阻滞剂的临床研究测试了它们缓解与BD、SCZ和药物依赖相关症状的疗效，结果不一，这凸显了进一步探索Ca1.2和Ca1.3失调的神经生物学后果的重要性。在此，我们综述了评估LTCC阻滞剂对BD、SCZ和药物依赖相关症状疗效的临床研究，以及确定了情绪（焦虑、抑郁）、社会行为、认知和成瘾背后的Ca1.2和Ca1.3特异性分子和细胞级联反应的啮齿动物研究。
