Prenatal THC exposure linked to stress-sensitive memory deficits

BACKGROUND: Stress is a major determinant of psychopathology in which coping and cognitive impairment arise from abnormal glucocorticoid activity and brain derived neurotrophic factor (BDNF)-dependent neuroplasticity in the hippocampus. The endocannabinoid system modulates stress and hippocampal functioning since early development, thus its early-life disruptions may program vulnerability to stress-related cognitive deficits. METHODS: We investigated whether prenatal exposure to tetrahydrocannabinol (pTHC; 2 mg/kg, gestational days 5-20) alters spatial learning and memory in adolescent offspring using the Morris water maze (MWM) Serum corticosterone and hippocampal mineralocorticoid/glucocorticoid receptor levels were measured at baseline and after MWM. Hippocampal plasticity was assessed through BDNF and its receptor expression and CA1 dendritic architecture. To probe the contribution of glucocorticoid signaling, corticosterone synthesis was inhibited with metyrapone (50 mg/kg, 7 days). RESULTS: pTHC offspring showed stress-related search strategy -thigmotaxis-, delayed learning, and impaired memory, accompanied by elevated glucocorticoid output and responsivity, reduced mineralocorticoid/glucocorticoid receptor ratio, decreased BDNF, and altered CA1 dendritic complexity. Metyrapone reduced thigmotaxis and rescued memory performance, normalizing glucocorticoid output, mineralocorticoid/glucocorticoid receptor balance, BDNF, and dendritic morphology. CONCLUSION: These findings demonstrate that prenatal THC exposure programs a stress-related vulnerability of hippocampal memory processes, which can be mitigated by reducing excessive glucocorticoid availability.