Yang Jian-Quan, Yang Chao-Hua, Yin Bao-Qi
Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Behav Brain Res. 2021 Apr 9;403:113094. doi: 10.1016/j.bbr.2020.113094. Epub 2021 Jan 29.
Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. In this study, we employed prenatally exposed to valproic acid (VPA) to establish a validated ASD mouse model and found impaired inhibitory gamma-aminobutyric acid (GABAergic) neurotransmission through a presynaptic mechanism in these model mice, which was accompanied with decreased GABA release and GABA-A and GABA-B receptor subunits expression. And acute administration of individual GABA-A or GABA-B receptor agonists partially reversed autistic-like behaviors in the model mice. Furthermore, acute administration of the combined GABA-A and GABA-B receptor agonists palliated sociability deficits, anxiety and repetitive behaviors in the animal model of autistic-like behaviors, demonstrating the therapeutic potential of above cocktail in the treatment of ASD.
自闭症谱系障碍（ASD）是一种极具挑战性的发育障碍，主要特征为社交沟通缺陷和局限/重复行为这两种核心行为症状。由于该疾病存在众多风险因素且症状复杂，研究其病因过程并确定合适的治疗靶点仍是克服ASD面临的巨大挑战。在导致ASD的各种机制中，维持兴奋与抑制平衡成为调节神经回路正常功能的关键因素。在本研究中，我们通过产前暴露于丙戊酸（VPA）建立了一个经过验证的ASD小鼠模型，并发现这些模型小鼠通过突触前机制存在抑制性γ-氨基丁酸（GABA能）神经传递受损的情况，这伴随着GABA释放减少以及GABA-A和GABA-B受体亚基表达降低。单独急性给予GABA-A或GABA-B受体激动剂可部分逆转模型小鼠的自闭症样行为。此外，急性给予GABA-A和GABA-B受体激动剂组合可缓解自闭症样行为动物模型中的社交缺陷、焦虑和重复行为，证明上述联合用药在治疗ASD方面具有治疗潜力。
