State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China.
The Ministry of Education of China, School of Basic Medical Sciences, Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China.
Nat Commun. 2021 May 31;12(1):3321. doi: 10.1038/s41467-021-23843-0.
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca release from intracellular Ca stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD.
自闭症谱系障碍（ASD）是一种常见的神经发育障碍。ASD 的发病机制尚不清楚。在 ASD 患者和动物模型中均观察到星形胶质细胞改变。然而，星形胶质细胞功能障碍是否是导致小鼠类似 ASD 表型的原因，目前尚未解决。2 型肌醇 1,4,5-三磷酸 6 受体（IP3R2）介导的细胞内钙库中的 Ca2+释放导致星形胶质细胞激活。IP3R2 基因突变与 ASD 有关。在这里，我们发现 IP3R2 基因缺失突变小鼠和星形胶质细胞特异性 IP3R2 条件性敲除小鼠均表现出 ASD 样行为，如社交互动异常和重复行为。此外，我们发现星形胶质细胞衍生的 ATP 通过前额叶皮层中的 P2X2 受体和可能通过 GABA 能突触传递来调节 ASD 样行为。这些发现确定了星形胶质细胞衍生的 ATP 是 ASD 病理生理学中的一个潜在分子参与者。
