Behavioral Neuroscience, Experimental and Biological Psychology, Department of Psychology, Philipps-Universität Marburg, Marburg, Germany.
Institute of Pharmacology and Clinical Pharmacy, Philipps-Universität Marburg, Marburg, Germany.
Genes Brain Behav. 2020 Feb;19(2):e12552. doi: 10.1111/gbb.12552. Epub 2019 Jan 15.
As cross-disorder risk gene, CACNA1C is implicated in the etiology of all major neuropsychiatric disorders characterized by deficits in social behavior and communication and there is evidence for sex-dependent influences of single-nucleotide polymorphisms within CACNA1C on diagnosis, course, and recovery in humans. In this study, we aimed, therefore, at further exploring the role of Cacna1c in regulating behavioral phenotypes, focusing on sex-specific differences in social behavior and communication during the critical developmental period of adolescence in rats. Specifically, we compared rough-and-tumble play, concomitant emission of pro-social 50-kHz ultrasonic vocalizations, and social approach behavior in response to playback of 50-kHz ultrasonic vocalizations between constitutive heterozygous Cacna1c females and wildtype Cacna1c littermate controls, and contrasted present female findings to data previously reported in males. Our results show for the first time that partial depletion of Cacna1c leads to sex-dependent alterations in social behavior and communication in rats. In females, Cacna1c haploinsufficiency led to hypermasculinization, with rough-and-tumble play behavior, in general, and pinning behavior, in particular, being even higher than in males without affecting concomitant 50-kHz ultrasonic vocalizations. In males, in contrast, rough-and-tumble play behavior was not altered, yet emission of 50-kHz ultrasonic vocalizations was diminished following partial Cacna1c depletion. The behavioral responses elicited by playback of 50-kHz ultrasonic vocalizations were reduced upon partial Cacna1c depletion in both sexes. It thus can be concluded that Cacna1c plays a prominent sex-dependent role in regulating juvenile rat social play behavior and pro-social 50-kHz ultrasonic communication with relevance to sex-specific effects seen in neuropsychiatric disorders.
作为跨疾病风险基因，CACNA1C 与以社会行为和交流缺陷为特征的所有主要神经精神疾病的发病机制有关，并且有证据表明 CACNA1C 内的单核苷酸多态性对人类的诊断、病程和恢复有性别依赖性影响。因此，在这项研究中，我们旨在进一步探索 Cacna1c 在调节行为表型中的作用，重点关注青春期大鼠关键发育阶段的社会行为和交流中的性别特异性差异。具体来说，我们比较了组成型杂合子 Cacna1c 雌性大鼠和野生型 Cacna1c 同窝对照大鼠的打闹嬉戏、同时发出亲社会的 50-kHz 超声波发声以及对 50-kHz 超声波发声的社会趋近行为，并将目前的女性研究结果与之前在雄性大鼠中报告的数据进行了对比。我们的研究结果首次表明，Cacna1c 的部分缺失会导致大鼠的社会行为和交流出现性别依赖性改变。在雌性大鼠中，Cacna1c 半不足导致雄性化过度，总体上的打闹嬉戏行为，特别是钉扎行为，甚至高于没有影响同时发出的 50-kHz 超声波发声的雄性大鼠。相比之下，雄性大鼠的打闹嬉戏行为没有改变，但部分 Cacna1c 缺失后，50-kHz 超声波发声减少。在两性大鼠中，部分 Cacna1c 缺失后，对 50-kHz 超声波发声的反应行为减少。因此，可以得出结论，Cacna1c 在调节幼年大鼠社会嬉戏行为和亲社会 50-kHz 超声波交流中发挥着重要的性别依赖性作用，与神经精神疾病中观察到的性别特异性影响有关。
