Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice

Qian Wang, Ying Kong, Ding-Yu Wu, Ji-Hong Liu, Wei Jie, Qiang-Long You, Lang Huang, Jian Hu, Huai- De Chu, Feng Gao, Neng-Yuan Hu, Zhou-Cai Luo, Xiao-Wen Li, Shu-Ji Li, Zhao-Fa Wu, Yu-Long Li, Jian-Ming Yang () and Tian-Ming Gao ()
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Qian Wang: Southern Medical University
Ying Kong: Southern Medical University
Ding-Yu Wu: Southern Medical University
Ji-Hong Liu: Southern Medical University
Wei Jie: Southern Medical University
Qiang-Long You: Southern Medical University
Lang Huang: Southern Medical University
Jian Hu: Southern Medical University
Huai- De Chu: Southern Medical University
Feng Gao: 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
Neng-Yuan Hu: Southern Medical University
Zhou-Cai Luo: Southern Medical University
Xiao-Wen Li: Southern Medical University
Shu-Ji Li: Southern Medical University
Zhao-Fa Wu: State Key Laboratory of Membrane Biology, Peking University School of Life Sciences
Yu-Long Li: State Key Laboratory of Membrane Biology, Peking University School of Life Sciences
Jian-Ming Yang: Southern Medical University
Tian-Ming Gao: Southern Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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 Ca2+ release from intracellular Ca2+ 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.

Date: 2021
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DOI: 10.1038/s41467-021-23843-0

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