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

作者：Wang, Qian; Kong, Ying; Wu, Ding-Yu; Liu, Ji-Hong; Jie, Wei; You, Qiang-Long; Huang, Lang; Hu, Jian; Chu, Huai-De; Gao, Feng; Hu, Neng-Yuan; Luo, Zhou-Cai; Li, Xiao-Wen; Li, Shu-Ji; Wu, Zhao-Fa; Li, Yu-Long; Yang, Jian-Ming^*; Gao, Tian-Ming^*

来源：Nature Communications, 2021, 12(1): 3321.

DOI：10.1038/s41467-021-23843-0

• INHIBITORY SYNAPTIC-TRANSMISSION
• LONG-TERM POTENTIATION
• RARE DE-NOVO
• P2X RECEPTORS
• TRPA1 CHANNELS
• ATP
• BRAIN
• EXPRESSION
• RELEASE
• PLASTICITY

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. Astrocytes contribute to autism spectrum disorder (ASD) pathophysiology. Here, the authors show that IP3R2 conditional KO mice show ASD-like behaviours and identify astrocyte-derived ATP as a modulator of these behaviours in mice.

• 单位
  广州医学院; 北京大学; 南方医科大学