Kami-shoyo-san improves ASD-like behaviors caused by decreasing allopregnanolone biosynthesis in an SKF mouse model of autism
Kami-shoyo-san improves ASD-like behaviors caused by decreasing allopregnanolone biosynthesis in an SKF mouse model of autism
复制标题
DOI：
10.1371/journal.pone.0211266
复制
发表时间：
2019-01-31
期刊：
影响因子：
3.7
通讯作者：
Matsumoto, Kinzo
中科院分区：
文献类型：
--
作者：
Guo, Qing-Yun;Ebihara, Ken;Matsumoto, Kinzo
GABA 能系统的功能障碍与自闭症谱系障碍 (ASD) 的发病机制有关。然而，GABA 能系统功能障碍诱发 ASD 病理生理学的机制仍不清楚。我们之前证明，选择性 I 型 5a 还原酶抑制剂 SKF105111 (SKF) 会在雄性小鼠中诱导类似 ASD 的行为，例如社交相关表现受损和重复梳理行为。此外，SKF 的作用是由于四氢孕酮 (ALLO) 的内源性水平降低引起的，ALLO 是 GABA(A) 受体的正变构调节剂。在这项研究中，我们使用 SKF 治疗的雄性小鼠作为假定的 ASD 动物模型，并检查了 Kami-shoyo-san (KSS) 作为 ASD 实验性治疗策略的效果。 KSS是一种传统的汉方配方，由10种不同的生药组成，已用于治疗神经精神症状。 KSS 剂量依赖性地减弱 SKF 治疗小鼠的社交能力缺陷并抑制梳理行为的增加，而不影响前额皮质中的 ALLO 含量。多巴胺 D-1 受体拮抗剂 SCH23390 的全身给药逆转了 KSS 的改善作用。另一方面，多巴胺 D-2 受体拮抗剂舒必利和 GABA(A) 受体拮抗剂荷包牡丹碱仅减弱 KSS 对重复性自我梳理行为的改善作用。目前的结果表明，KSS 通过促进多巴胺受体介导的机制以及部分通过神经类固醇独立的 GABA(A) 受体介导的神经传递来改善 SKF 诱导的 ASD 样行为。因此，KSS 是治疗 ASD 的潜在候选者。
Dysfunctions in the GABAergic system are associated with the pathogenesis of autism spectrum disorder (ASD). However, the mechanisms by which GABAergic system dysfunctions induce the pathophysiology of ASD remain unclear. We previously demonstrated that a selective type I 5a-reductase inhibitor SKF105111 (SKF) induced ASD-like behaviors, such as impaired sociability-related performance and repetitive grooming behaviors, in male mice. Moreover, the effects of SKF were caused by a decrease in the endogenous levels of allopregnanolone (ALLO), a positive allosteric modulator of the GABA(A) receptor. In this study, we used SKF-treated male mice as a putative animal model of ASD and examined the effects of Kami-shoyo-san (KSS) as an experimental therapeutic strategy for ASD. KSS is a traditional Kampo formula consisting of 10 different crude drugs and has been used for the treatment of neuropsychiatric symptoms. KSS dose-dependently attenuated sociability deficits and suppressed an increase in grooming behaviors in SKF-treated mice without affecting ALLO content in the prefrontal cortex. The systemic administration of the dopamine D-1 receptor antagonist SCH23390 reversed the ameliorative effects of KSS. On the other hand, the dopamine D-2 receptor antagonist sulpiride and GABA(A) receptor antagonist bicuculline only attenuated the ameliorative effect of KSS on repetitive self-grooming behaviors. The present results indicate that KSS improves SKF-induced ASD-like behaviors by facilitating dopamine receptor-mediated mechanisms and partly by neurosteroid-independent GABA(A) receptor-mediated neurotransmission. Therefore, KSS is a potential candidate for the treatment of ASD.