AUTISTIC-LIKE BEHAVIORS MEDIATED BY THE DYSREGULATION OF ENDOCRINE SYSTEMS VIA OXYTOCIN AND CORTICOSTERONE IN CANNABINOID CB1 RECEPTOR KNOCKOUT MICE

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disability that demonstrates impaired social interactions, social communication deficits, and restrictive/repetitive behaviors. Children with ASD in some cases have comorbid disorders such as anxiety and/or learning disabilities. Recent evidences have reported that children with ASD and some animal models of ASD show abnormalities of endocannabinoid (eCB) system. To determine the causal role of the eCB systems in the ASD, we investigated the relationship between the eCB system and ASD-like symptoms, using the cannabinoid CB1 receptor knockout (CB1KO) mice. Social behaviors and repetitive grooming behaviors which reflect for core symptoms of ASD were evaluated with 3-chambered social approach task and hole-board test.

Learning and memory was also evaluated with Y-maze test and reversal learning task using T-maze. We found that CB1KO mice demonstrated reduced sociability and elevated repetitive grooming behaviors compared to wild-type mice. CB1KO mice also showed decline of alteration in Y-maze test and resistance to change a learned pattern of behavior in T-maze reversal task. We next measured serum corticosterone and serum/brain oxytocin, expected as biomarkers for ASD. As a result, serum corticosterone significantly increased in CB1KO mice. In contrast, both serum and brain (hippocampus and hypothalamus) oxytocin were decreased in CB1KO mice. Based on these results, we next attempted to recover the autistic-like behaviors in CB1KO mice. Then, single administration of LIT-001 (10 mg/kg, i.p.), an oxytocin receptor agonist, or SSR125543A (10 mg/kg, i.p.), a type 1 corticotropin-releasing factor (CRF1) receptor antagonist, significantly ameliorated the decrease of sociability and elevated repetitive behaviors in CB1KO mice. These results suggest that the endocrine abnormalities are involved in the expression of autistic-like behaviors observed in CB1KO mice. Therefore, CB1KO mice could have potential as a novel ASD model mouse and provide possibilities of drug development for ASD using the oxytocin receptor agonist and CRF1 receptor antagonist.