Adolescent Δ9-Tetrahydrocannabinol Exposure and Astrocyte-Specific Genetic Vulnerability Converge on Nuclear Factor-κB-Cyclooxygenase-2 Signaling to Impair Memory in Adulthood

BACKGROUND: Although several studies have linked adolescent cannabis use to long-term cognitive dysfunction, there are negative reports as well. The fact that not all users develop cognitive impairment suggests a genetic vulnerability to adverse effects of cannabis, which are attributed to action of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), a cannabis constituent and partial agonist of brain cannabinoid receptor 1. As both neurons and glial cells express cannabinoid receptor 1, genetic vulnerability could influence Delta(9)-THC-induced signaling in a cell type-specific manner. METHODS: 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 interact with adolescent Delta(9)-THC exposure to impair recognition memory in adulthood. RESULTS: Selective expression of DN-DISC1 in astrocytes and adolescent treatment with Delta(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 Delta(9)-THC during adolescence. At the molecular level, DN-DISC1 and Delta(9)-THC synergistically activated the nuclear factor-kappa B-cyclooxygenase-2 pathway in astrocytes and decreased immunoreactivity of parvalbumin-positive presynaptic inhibitory boutons around pyramidal neurons of the hippocampal CA3 area. The cognitive abnormalities were prevented in DN-DISC1 mice exposed to Delta(9)-THC by simultaneous adolescent treatment with the cyclooxygenase-2 inhibitor, NS398. CONCLUSIONS: 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 Delta(9)-THC-produced cognitive impairments via convergent inflammatory signaling, suggesting possible targets for preventing adverse effects of cannabis within susceptible individuals.