Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
School of Psychology, Cardiff University, Cardiff, UK.
Schizophr Bull. 2019 Sep 11;45(5):1024-1032. doi: 10.1093/schbul/sby146.
Genetic variation in CACNA1C, which encodes the alpha-1 subunit of Cav1.2 L-type voltage-gated calcium channels (VGCCs), has been strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. How genetic variation in CACNA1C contributes to risk for these disorders is however not fully known. Both schizophrenia and bipolar disorder are associated with impairments in reversal learning (RL), which may contribute to symptoms seen in these conditions. We used a translational RL paradigm to investigate whether genetic variation in CACNA1C affects RL in both humans and transgenic rats. Associated changes in gene expression were explored using in situ hybridization and quantitative PCR in rats and the BRAINEAC online human database. Risk-associated genetic variation in CACNA1C in healthy human participants was associated with impairments in RL. Consistent with this finding, rats bearing a heterozygous deletion of Cacna1c were impaired in an analogous touchscreen RL task. We investigated the possible molecular mechanism underlying this impairment and found that Cacna1c +/- rats show decreased expression of Bdnf in prefrontal cortex. Examination of BRAINEAC data showed that human risk-associated genetic variation in CACNA1C is also associated with altered expression of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex in humans. These results indicate that genetic variation in CACNA1C may contribute to risk for schizophrenia and bipolar disorder by impacting behavioral flexibility, potentially through altered regulation of BDNF expression in the prefrontal cortex. Tests of RL may be useful for translational studies and in the development of therapies targeting VGCCs.
CACNA1C 基因中的遗传变异，该基因编码 Cav1.2 L 型电压门控钙通道（VGCC）的α-1 亚基，与包括精神分裂症和双相情感障碍在内的精神疾病的风险密切相关。然而，CACNA1C 中的遗传变异如何导致这些疾病的风险尚不完全清楚。精神分裂症和双相情感障碍都与反转学习（RL）受损有关，这可能导致这些疾病出现症状。我们使用转化 RL 范式来研究 CACNA1C 中的遗传变异是否会影响人类和转基因大鼠的 RL。使用原位杂交和定量 PCR 研究了大鼠中的基因表达变化，并在 BRAINEAC 在线人类数据库中进行了研究。健康人类参与者 CACNA1C 中的风险相关遗传变异与 RL 受损有关。与这一发现一致，携带 Cacna1c 杂合缺失的大鼠在类似的触摸屏 RL 任务中受损。我们研究了这种损伤的潜在分子机制，发现 Cacna1c +/-大鼠在前额叶皮层中表现出 Bdnf 表达减少。对 BRAINEAC 数据的检查表明，CACNA1C 中的人类风险相关遗传变异也与人类前额叶皮层中脑源性神经营养因子（BDNF）表达的改变有关。这些结果表明，CACNA1C 中的遗传变异可能通过改变前额叶皮层中 BDNF 的表达，从而影响行为灵活性，从而导致精神分裂症和双相情感障碍的风险增加。RL 的测试可能对转化研究和靶向 VGCC 的治疗方法的开发有用。
