187. ROLE OF THE ANTERIOR INSULA AND THE ENDOCANNABINOID SYSTEM IN AUTISM NEURODEVELOPMENTAL DISORDER

Abstract Background Autism spectrum disorder (ASD) is a complex multifactorial disorder, and the mechanisms involved are not well understood. The anterior insular cortex (IC) is an important communication hub in the brain, and a dysfunctional anterior IC has been associated with ASD. Aims & Objectives Here, we will investigate the involvement of the endocannabinoid system in the insular cortex in anxiety and social behaviors, two core phenotypes that are affected in ASD. Method To express the CB1R exclusively in the anterior IC, we used a viral approach to modify cell type-specific CB1R expression using a double-viral injection of Cre and Flex viral vectors. WT mice with the CB1R gene locus flanked by two loxP sites were injected in the IC with an AAV-[cell-type specific promoter, CamKII]-Cre and an AAV-DIO-CB1, mutant DN22-CB1 or control. Cell type specific-driven Cre expression excised the CB1R gene in glutamatergic neurons and the DIO (Flex) virus was used to rescue the expression of those receptors in a subcellular-compartment-specific manner. The dual viral vector approach was performed on day P21. After two weeks of AAV expression, a complete phenotypic characterization of the core and the co-morbid symptoms of ASD was performed in CB1 and Shank3 floxed mice. Results Interestingly, the expression of CB1Rs in the anterior IC restored the phenotype observed in CB1-KO mice. Differential expression of the CB1 receptor in glutamatergic neurons at distinct subcellular-compartment-specific levels, at the membrane and the mitochondria, produced different phenotypes in CB1 and Shank3 floxed mice. Discussion & Conclusions We have established a novel and reliable mouse model to study the involvement of the CB1Rs in the anterior IC. Elucidating novel mechanisms will add new insights into a more in-depth understanding of the brain pathways involved in the onset and development of ASD, which may open new therapeutic approaches.