Activation Of Astrocyte Cannabinoid Receptors Improves Autistic-Like Behavior In Mice

Autism spectrum disorder（ASD）is a common neurodevelopmental disorder that causes repetitive stereotyped behavior and social behavior disorder,which are the core symptoms plaguing people with autism,but the underlying pathogenesis of ASD is unknown,and there is no effective drug treatment.Cannabis has been used to treat a variety of diseases since ancient times,but with the development of modern medicine,the application of cannabinoids,the active ingredient of cannabis,has been limited in a variety of ways,mostly due to the addiction caused by cannabinoids and their side effects such as learning and memory impairment.The receptors of cannabinoids are mainly type Ⅰ cannabinoid receptor（CB1R）and type Ⅱ cannabinoid receptor（CB2R）,which are widely expressed on neurons and astrocytes,and in recent years there have been preclinical studies showing that the endocannabinoid system exhibits some beneficial properties for social disorders.The activation of astrocytes is mainly mediated by the release of Ca²⁺ from cells by the type 2 inositol 1,4,5-triphosphate receptor（Ip3r2）,the deletion of which causes astrocytes dysfunction,leading to the occurrence of autism.But whether cannabinoid receptors that activate astrocytes regulate their calcium activity and regulate autism-like behavior in mice is unclear.Here,we found that mice with systematic knockout of Ip3r2 or conditioned knockdown of Ip3r2 in medial prefrontal cortex（mPFC）exhibited autism-like behavior,and cannabinoid CP55940 could improve autistic behavior caused by Ip3r2 knockout.Cannabinoids increase calcium activity and release of calcium-dependent ATP in Ip3r2 deficient astrocytes.These suggest that activation of astrocyte cannabinoid receptors can improve autism-like behavior in Ip3r2-deficient mice by rescuing calciumdependent ATP release in astrocytes.Therefore,astrocyte cannabinoid system might be the target for therapeutic intervention in autism.