Ebihara Ken, Fujiwara Hironori, Awale Suresh, Dibwe Dya Fita, Araki Ryota, Yabe Takeshi, Matsumoto Kinzo
Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Behav Brain Res. 2017 Sep 15;334:6-15. doi: 10.1016/j.bbr.2017.07.019. Epub 2017 Jul 22.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABA receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD.
自闭症谱系障碍（ASD）是一种神经发育障碍，其核心症状为社交障碍和局限的重复行为。最近的证据表明，γ-氨基丁酸（GABA）能系统功能障碍与ASD的病理生理学有关。我们使用SKF105111（SKF），一种I型和II型5α-还原酶（ALLO生物合成的限速酶）的抑制剂，研究了内源性别孕烯醇酮（ALLO），一种GABA受体的神经甾体正变构调节剂，在雄性小鼠ASD样行为调节中的作用。通过三种不同的测试分析，SKF损害了与社交能力相关的表现；即三室测试、旷场中的社交互动以及定居者-入侵者测试，而不影响通过埋藏食物测试所阐明的嗅觉功能。SKF还诱导了重复梳理行为，而不影响焦虑样行为。SKF对短期空间工作记忆或长期恐惧记忆没有影响，但增强了雄性小鼠的潜在学习能力。通过全身给予ALLO（1mg/kg，腹腔注射）和哌甲酯（MPH：2.5mg/kg，腹腔注射），一种多巴胺转运体抑制剂，可消除SKF在雄性小鼠中诱导的ASD样行为。ALLO可逆转SKF对雄性小鼠脑内ALLO含量的影响，但MPH不能。另一方面，SKF未能在雌性小鼠中诱导ASD样行为或导致脑内ALLO含量下降。这些结果表明，ALLO通过正向调节与多巴胺能系统相关的GABA受体功能来调节ASD样行为发作。此外，脑内ALLO含量的性别依赖性降低可能为研究ASD的主要特征提供一种动物模型。
