Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry

Abstract

Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid system and the brain's fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3mg/kg) from gestational day (GD) 7 until GD22. Anxiety-like, depressive-like, and reward-seeking behaviour, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was performed at prepubescence and adulthood. We report PCE induces behavioral, neuronal, and molecular alterations in the mesolimbic system in male and female offspring, resembling neuropsychiatric endophenotypes. Additionally, PCE resulted in profound dysregulation of critical fatty acid pathways in the developing brain lipidome. Female progeny exhibited greater alterations to fatty acid levels at prepubescence but recovered from these deficits by early adulthood. In contrast, males exhibited persistent fatty acid deficits into adulthood. Moreover, both sexes maintained enduring abnormalities in glutamatergic/GABAergic function in the nucleus accumbens. These findings identify several novel longterm risks of maternal cannabis use and demonstrate for the first time, sex-related effects of maternal cannabinoid exposure directly in the developing neural lipidome. Significance StatementPrenatal cannabinoid exposure (PCE) is growing in prevalence and the long-term effects on fetal brain development are largely unknown. Our study provides novel evidence that chronic prenatal THC exposure can induce long-lasting alterations in mesolimbic function that differentially impacts the male vs. female brains. We also demonstrate for the first time that PCE can induce profound lipidomic adaptations that may account for these neuropathophysiological sequelae.

Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy

“…These neurochemical alterations might contribute to the higher susceptibility to develop neurodevelopmental and psychiatric disorders in the children of mothers who used Cannabis during pregnancy [ 28 , 29 , 222 , 224 ]. This conclusion is supported by many studies performed in animal models, in which a wide spectrum of behavioral and neural alterations have been reported in the offspring of dams prenatally exposed to Cannabis [ 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 ]. Interestingly, Rompala and colleagues recently found that emotional dysregulations in children whose mothers were Cannabis users are associated with increased stress hormone levels in the hair and, intriguingly, reduced immune-related gene expression in the placenta, suggesting that the atypical behavioral traits induced by prenatal Cannabis exposure might be partly linked to the immunosuppressive effects of cannabinoids [ 240 ].…”

Characterization of cannabinoid plasma concentration, maternal health, and cytokine levels in a rat model of prenatalCannabissmoke exposure

“…Levels of THC and CBD, as well as some of their metabolites, were significantly higher 30 min following repeated injections than repeated smoke exposure on GD20. In general, we chose to compare injected doses of THC and CBD commonly used in rodent models [38,39,42,[75][76][77][78] with the smoke inhalation protocol developed in our laboratory [57,68,79]. The inhalation protocol resembles other 'hotbox' methods [72,80,81], and has been shown to result in acute behavioural and oscillatory effects [68,79], as well as long-term changes in the offspring following exposure during pregnancy [57].…”

Characterization of cannabinoid plasma concentration, maternal health, and cytokine levels in a rat model of prenatal Cannabis smoke exposure

“…Levels of THC and CBD, as well as some of their metabolites, were significantly higher 30 min following repeated injections than repeated smoke exposure on GD20. In general, we chose to compare injected doses of THC and CBD commonly used in rodent models 41,42,45,49,51,[103][104][105][106] , with the smoke inhalation protocol developed in our laboratory 81,[93][94][95] . The inhalation protocol resembles other 'hotbox' methods 100,101,107 , and has been shown to result in acute behavioural and oscillatory effects [93][94][95] , as well as long-term changes in the offspring following exposure during pregnancy 81 .…”