Kami-shoyo-san improves ASD-like behaviors caused by decreasing allopregnanolone biosynthesis in an SKF mouse model of autism

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 5α-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 GABAA 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 D1 receptor antagonist SCH23390 reversed the ameliorative effects of KSS. On the other hand, the dopamine D2 receptor antagonist sulpiride and GABAA 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 GABAA receptor-mediated neurotransmission. Therefore, KSS is a potential candidate for the treatment of ASD.

γ-氨基丁酸能系统（GABAergic system）功能异常与自闭症谱系障碍（ASD）的发病机制密切相关。然而，γ-氨基丁酸能系统功能异常诱发ASD病理生理改变的具体机制仍未明确。本团队前期研究证实，I型5α-还原酶抑制剂SKF105111（简称SKF）可诱导雄性小鼠出现类ASD样行为，包括社交相关行为受损与重复性理毛行为。进一步研究表明，SKF的上述效应源于内源性别孕烯醇酮（ALLO）水平降低——后者是GABAA受体的正变构调节剂。本研究以SKF处理的雄性小鼠作为ASD潜在动物模型，探究加味逍遥散（Kami-shoyo-san, KSS）作为ASD实验性治疗策略的效果。KSS是一种由10种不同生药组成的传统汉方方剂，既往被用于治疗神经精神症状。实验结果显示，KSS可剂量依赖性缓解SKF处理小鼠的社交缺陷，并抑制其理毛行为增多的现象，且不会改变小鼠前额叶皮层内的ALLO水平。多巴胺D1受体拮抗剂SCH23390可完全逆转KSS的改善效应；而多巴胺D2受体拮抗剂舒必利（sulpiride）与GABAA受体拮抗剂荷包牡丹碱（bicuculline）仅能部分缓解KSS对重复性自我理毛行为的改善作用。本研究结果表明，KSS可通过激活多巴胺受体介导的信号通路，以及部分依赖于神经甾体非依赖型GABAA受体介导的神经传递，改善SKF诱导的类ASD样行为。因此，KSS有望成为ASD治疗的潜在候选药物。