Adolescent Exposure to a THC ‐Rich Cannabis Extract Produces Genotype‐Dependent Effects on Cognition and Glial Morphology in Serine Racemase Mutant Mice

ABSTRACT

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. Δ ⁹ ‐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.

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