Cannabidiol-Induced Recovery of Social Behaviour in Mouse Models of Syndromic Autism

Despite the growing prevalence of autism, no pharmacological interventions have been approved for core symptoms. The endocannabinoid system (ECS) has recently gained interest as a potential target for treating autism. Cannabidiol (CBD), a compound found in the Cannabis plant (C. Sativa), is a potential autism treatment due to its tolerability and promising early results in fragile X syndrome patients. Here, we aimed to evaluate the efficacy of CBD in treating social deficits and restrictive/repetitive behaviours in two monogenetic models of autism, Shank3 and Fmr1 knock-out (KO) mice. Male and female mice were tested in the 3-chamber social apparatus or for self-grooming and open field test (baseline or pre-treatment), followed by 5 daily treatments of vehicle or CBD (s.c., 5mg/kg for males, 50mg/kg for females) and tested again after the last injection (post-treatment). At baseline and following vehicle treatment, male and female Shank3 and Fmr1 KO mice exhibited deficits in social novelty, which were restored to control levels following CBD administration. Meanwhile, self-grooming (increased in male and female Shank3 KO mice) and open-field exploration (decreased locomotion in Shank3 KO mice) were not affected by CBD. Females had hippocampal CBD levels ~11.6 times higher than males (concordant with the dosing) and presented elevated levels of anandamide (AEA) in the CBD-treated groups. Transcriptomic analysis of the hippocampus revealed a lack of overlap in the CBD differentially expressed genes (DEGs) among the different strains and between sexes. These results suggest sex- and strain-specific mechanisms for CBD and support its therapeutic effects for syndromic autism. Overall design: RNA-Seq profiling of hippocampal tissue collected from male and female wildtype, Shank3 knockout, and Fmr1 KO mice treated with vehicle or CBD