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

Rangel I.; Chaves M.; Pagnoncelli I.; Medeiros I.; Pinheiro F.; Fortuna L.; Castello-Branco L.; Roch E.; Carvalho V.; Lima F. et al. · Journal of neurochemistry · 2026

**Background & Methods** This preclinical study investigated how adolescent exposure to THC-rich cannabis extract affected long-term neurobehavioral and neurochemical outcomes in serine racemase mutant (SrrY269*) mice—a genetic model of reduced D-serine availability relevant to schizophrenia pathophysiology—compared to wild-type controls. Adolescent mice received escalating oral doses of the extract and were evaluated in adulthood using behavioral assays (prepulse inhibition, spatial memory, open field testing), amino acid quantification, and glial morphometric analyses. **Key Findings** • **Genotype-dependent behavioral effects**: Adolescent THC-rich extract exposure prevented prepulse inhibition and spatial object recognition memory deficits in adult SrrY269* mice but transiently impaired sensorimotor gating in wild-type animals, indicating protective effects in the genetic model but adverse effects in normal mice. • **Glial morphology alterations**: SrrY269* mice showed attenuated microglial branching deficits and astrocytic morphological abnormalities following adolescent treatment; conversely, wild-type mice exhibited distinct adverse astrocytic phenotype changes from the same exposure. • **Increased center-field exploration**: Regardless of genotype, treated mice spent more time in open field centers in adulthood, suggesting altered anxiety-related behavior across both groups. **Dosage & Administration** Escalating oral doses of THC-rich cannabis extract administered during adolescence; specific dose ranges not reported. **Safety & Adverse Effects** Transient sensorimotor gating impairment in wild-type animals; induction of distinct astrocytic morphological changes in wild-type mice. D-serine and NMDAR-related amino acid levels remained unaltered in hippocampus and prefrontal cortex, suggesting mechanisms independent of direct D-serine pathway modulation. **Evidence Quality** This animal model study demonstrates moderate internal validity but significant translational limitations. The SrrY269* mouse model, while relevant to schizophrenia-related phenotypes, may not fully recapitulate human genetic vulnerability. Findings are limited by lack of behavioral-naive cohort data for all measurements, single cannabis extract formulation tested, and unknown applicability to human adolescent cannabis exposure. The study provides preliminary evidence that genetic background influences THC developmental neurotoxicity but requires human prospective studies for clinical relevance.

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