Microglial cannabinoid receptor type 1 mediates social memory deficits produced by adolescent THC exposure and 16p11.2 duplication

Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals. Overall design: We performed RNA sequencing (RNA-seq)-based analyses to determine transcriptome changes in the microglia produced by adolescent THC treatment and 16p11dup. We isolated CD11b+/CD45+/P2ry12+ microglia from the mPFC at P51 using fluorescence-activated cell sorting (FACS). FACS-isolated microglia were subjected to RNA-seq analysis using the Smart-seq2 protocol that is applicable for a limited number of FACS-collected cells with full-length coverage.