The Neurodevelopmental Consequences of Prenatal Cannabinoid Exposure: Pathological Impacts in the Mesocorticolimbic System and Exploratory Therapeutic Interventions

Prenatal exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, poses significant neurodevelopmental risks. Extensive research, encompassing preclinical models and epidemiological analyses, consistently demonstrates the adverse outcomes associated with prenatal cannabinoid exposure (PCE). The endocannabinoid system (ECS), particularly within the mesocorticolimbic circuit, is critical for cognitive and emotional regulation. PCE-induced disruptions in ECS signaling can dysregulate neurotransmitter activity, notably within GABAergic, glutamatergic, and dopaminergic systems, heightening the risk of psychiatric disorders. Moreover, PCE is linked to symmetrical fetal growth restriction (FGR) due to compromised placental function, leading to reduced nutrient and oxygen delivery to the fetus, thereby impairing brain development. The resulting insufficiency in placental transfer of essential polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and arachidonic acid (AA), both critical for ECS function, exacerbates these neurodevelopmental disturbances. We hypothesized that PCE leads to disturbances in gestational brain development, resulting in abnormal neurocognition and altered neural fatty acid profiles in later life. We employed a comprehensive set of tools, including behavioral assays to assess cognition/memory and emotional regulation, in vivo extracellular electrophysiology, molecular protein assessments, and matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS). MALDI IMS enabled the assessment of the neural lipidome, and metabolomic changes, focusing on GABA, glutamate, and dopamine. Our research, utilizing a rodent model of prenatal THC exposure, identifies sex-specific alterations in neurotransmitter activity within the nucleus accumbens (NAc), basolateral amygdala (BLA), ventral tegmental area (VTA), prefrontal cortex (PFC), and ventral hippocampus (vHIPP). Our findings revealed a disturbed neuronal phenotype in male progeny in all regions assessed, while female progeny exhibited deficits primarily in the PFC-vHIPP circuit. Interventions with omega-3 supplementation during the perinatal period, and the antioxidant L-Theanine during adolescence, targeting lipidomic and excitotoxic hyperglutamatergic abnormalities respectively, demonstrated promising preventive effects on PCE-induced behavioral and electrophysiological disturbances. These findings highlight the complex impact of PCE on neurodevelopment, emphasizing the potential for targeted interventions to mitigate its adverse effects. Together, these studies provide critical new insights into the role of the ECS and its interactions with fatty acids in regulating mammalian neurodevelopmental processes and associated phenomena in the mesocorticolimbic system.