Adolescent Exposure to a THC-Rich Cannabis Extract Produces Genotype-Dependent Effects on Cognition and Glial...

Adolescent cannabis exposure has been associated with an increased risk of schizophrenia; however, how genetic vulnerability shapes the long-term consequences of adolescent cannabinoid exposure remains poorly understood. Δ⁹-Tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis and the predominant cannabinoid in the THC-rich cannabis extract used here, primarily activates cannabinoid type 1 receptors (CB1). In parallel, reduced availability of D-serine, an endogenous co-agonist of N-methyl-D-aspartate receptors (NMDARs), has been implicated in the pathophysiology of schizophrenia. Here, we investigated whether adolescent exposure to a THC-rich cannabis extract modulated long-term behavioral, neurochemical, and glial outcomes in serine racemase mutant (SrrY269*) mice, a genetic model characterized by reduced D-serine levels and schizophrenia-relevant phenotypes. Mice received escalating oral doses of the THC-rich cannabis extract during adolescence and were evaluated in adulthood using behavioral assays, amino acid quantification, and glial morphometric analyses. Adolescent exposure to the THC-rich cannabis extract prevented deficits in prepulse inhibition and spatial object recognition memory in adult SrrY269* mice, while transiently impairing sensorimotor gating in wild-type animals. Irrespective of genotype, mice exposed to the THC-rich cannabis extract spent more time in the center of the open field in adulthood. In behaviorally tested SrrY269* mice, reduced hippocampal microglial branching was attenuated following adolescent treatment. In an independent behavior-naïve cohort, SrrY269* mice exhibited marked astrocytic morphological alterations, several of which were also attenuated by adolescent exposure to the THC-rich cannabis extract. In contrast, the same treatment induced a distinct astrocytic phenotype in wild-type mice. Adolescent exposure to the THC-rich cannabis extract did not alter hippocampal or prefrontal cortical levels of D-serine or other amino acids involved in NMDAR signaling in adulthood. These findings indicate that adolescent exposure to a THC-rich cannabis extract produces genotype-dependent long-term effects, preventing specific behavioral deficits and attenuating independently assessed microglial and astrocytic alterations in SrrY269* mice, while producing adverse behavioral and astrocytic outcomes in wild-type animals. Genetic background may therefore be an important determinant of the long-term neurodevelopmental consequences of adolescent exposure to THC-rich cannabis extracts.