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.
Highlights
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder
In postmortem brain tissue from donors affected by ASD, the altered expression of astrocyte markers, such as glial fibrillary acidic protein (GFAP), S100β, aquaporin-4, connexin 43 and excitatory amino acid transporter 1, has been reported;[6,7,8,9,10,11,12,13] similar findings have been reported in animal models of autism[14,15]
Disturbance of intracellular calcium signals induced by a Gq-linked G protein-coupled receptors (GPCRs) agonist cocktail in astrocytes, but not neurons, from IP3R2 KO mice was confirmed in our previous study[21]
Summary
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. 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. Using induced pluripotent stem cells from patients affected by ASD, recent studies have further demonstrated that human induced pluripotent stem cells-derived astrocytes compromise neuronal development; in contrast, control-derived astrocytes rescue the morphological and synaptic defects of ASD neuronal cocultures[16,17] These findings suggest that astrocytes may be involved in the pathological process of ASD. By taking advantage of IP3R2 null and Aldh1l1::CreER – IP3R2 floxed animals with impaired astrocytic IP3R2-mediated signaling, we demonstrate that astrocyte-derived ATP is involved in the modulation of ASD-like behaviors in mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
