Adolescent ?9-THC exposure and astrocyte-specific genetic vulnerability converge on NF-?B-COX-2 signaling to impair memory in adulthood

Adolescent cannabis use has been associated with long-term cognitive dysfunction attributed to action of the main cannabis ingredient, delta-9-tetrahydrocannabinol (?9-THC), on the cannabinoid receptor 1 (CNR1). However, not all marijuana users develop cognitive impairment, suggesting a genetic vulnerability to adverse effects of cannabis. As both neurons and glial cells express CNR1, genetic vulnerability could influence ?9-THC-induced signaling in a cell type-specific manner. Here we use an animal model of inducible expression of dominant-negative Disrupted-In-Schizophrenia-1 (DN-DISC1) selectively in astrocytes to evaluate the molecular mechanisms whereby an astrocyte genetic vulnerability could synergistically interact with adolescent ?9-THC exposure to impair recognition memory in adulthood. We report that selective expression of DN-DISC1 in astrocytes and adolescent treatment with ?9-THC synergistically affected recognition memory in adult mice. Similar deficits in recognition memory were observed following knockdown of endogenous Disc1 in hippocampal astrocytes in mice treated with ?9-THC during adolescence. At the molecular level, DN-DISC1 and ?9-THC synergistically activated the NF-kB-COX-2 (encoded by Ptgs2 gene) pathway in astrocytes and decreased immunoreactivity of parvalbumin-positive pre-synaptic inhibitory boutons around pyramidal neurons of the CA3 area of the hippocampus. The cognitive abnormalities were prevented in DN-DISC1 mice exposed to ?9-THC by simultaneous adolescent treatment with the COX-2 inhibitor, NS389. Our data demonstrate that individual vulnerability to cannabis can be exclusively mediated by astrocytes. Results of this work suggest that genetic predisposition within astrocytes can exaggerate ?9-THC-produced cognitive impairments via convergent inflammatory signaling, suggesting possible targets for preventing adverse effects of cannabis within susceptible individuals. Overall design: Gene expression in hippocampus assayed in control and aDN-DISC1 mice treated with vehicle or ?9-THC (four groups, n=3 per group)