Kotajima-Murakami Hiroko, Hagihara Hideo, Sato Atsushi, Hagino Yoko, Tanaka Miho, Katoh Yoshihisa, Nishito Yasumasa, Takamatsu Yukio, Uchino Shigeo, Miyakawa Tsuyoshi, Ikeda Kazutaka
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-Ku, Japan.
Department of Biosciences, School of Science and Engineering, Teikyo University, Utsunomiya-Shi, Japan.
Front Psychiatry. 2022 Feb 3;13:821354. doi: 10.3389/fpsyt.2022.821354. eCollection 2022.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by impairments in social interaction and restricted/repetitive behaviors. The neurotransmitter γaminobutyric acid (GABA) through GABA receptor signaling in the immature brain plays a key role in the development of neuronal circuits. Excitatory/inhibitory imbalance in the mature brain has been investigated as a pathophysiological mechanism of ASD. However, whether and how disturbances of GABA signaling in embryos that are caused by GABA receptor inhibitors cause ASD-like pathophysiology are poorly understood. The present study examined whether exposure to the GABA receptor antagonist picrotoxin causes ASD-like pathophysiology in offspring by conducting behavioral tests from the juvenile period to adulthood and performing gene expression analyses in mature mouse brains. Here, we found that male mice that were prenatally exposed to picrotoxin exhibited a reduction of active interaction time in the social interaction test in both adolescence and adulthood. The gene expression analyses showed that picrotoxin-exposed male mice exhibited a significant increase in the gene expression of odorant receptors. Weighted gene co-expression network analysis showed a strong correlation between social interaction and enrichment of the "odorant binding" pathway gene module. Our findings suggest that exposure to a GABA receptor inhibitor during the embryonic period induces ASD-like behavior, and impairments in odorant function may contribute to social deficits in offspring.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征在于社交互动受损以及存在受限/重复行为。神经递质γ-氨基丁酸（GABA）通过未成熟大脑中的GABA受体信号传导，在神经元回路的发育中起关键作用。成熟大脑中的兴奋/抑制失衡已被作为ASD的一种病理生理机制进行研究。然而，由GABA受体抑制剂引起的胚胎期GABA信号传导紊乱是否以及如何导致ASD样病理生理学，目前尚不清楚。本研究通过从幼年期到成年期进行行为测试，并在成熟小鼠大脑中进行基因表达分析，来检测暴露于GABA受体拮抗剂印防己毒素是否会导致后代出现ASD样病理生理学。在此，我们发现产前暴露于印防己毒素的雄性小鼠在青春期和成年期的社交互动测试中，主动互动时间均减少。基因表达分析表明，暴露于印防己毒素的雄性小鼠气味受体的基因表达显著增加。加权基因共表达网络分析显示社交互动与“气味结合”途径基因模块的富集之间存在强相关性。我们的研究结果表明，胚胎期暴露于GABA受体抑制剂会诱发ASD样行为，并且气味功能受损可能导致后代出现社交缺陷。
