Date Published: January 31, 2019
Publisher: Public Library of Science
Author(s): Qing-Yun Guo, Ken Ebihara, Takafumi Shimodaira, Hironori Fujiwara, Kazufumi Toume, Dya Fita Dibwe, Suresh Awale, Ryota Araki, Takeshi Yabe, Kinzo Matsumoto, Joohyung Lee.
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.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder involving diagnostic behavioral criteria such as social and communicative impairments and restrictive repetitive behaviors . These symptoms often appear in the early stages of development  and are frequently comorbid with other diseases such as anxiety, depression, and attention deficit hyperactivity disorder (ADHD). Identified risk factors for ASD include genetic variations, epigenetic anomalies, and environmental factors , and the most critical risk factor for a cure are genetic variations. Hundreds of ASD-related genes have been detected, and mutations in these genes affect synaptic function, transcription factors, and neurotransmission [4–6].
We demonstrated that KSS improved ASD-like behaviors in SKF-treated male mice via the stimulation of dopaminergic and, partly, GABAA receptor mechanisms in the brain. These results not only support our hypothesis that ASD-like behaviors caused by a decrease in brain ALLO content are caused by an impaired link between the GABAergic and dopaminergic systems , but also provide a new potential therapeutic strategy for ASD using Kampo medicine.