TY - JOUR T1 - Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0253-22.2022 VL - 9 IS - 5 SP - ENEURO.0253-22.2022 AU - Mohammed H. Sarikahya AU - Samantha Cousineau AU - Marta De Felice AU - Kendrick Lee AU - Karen KW Wong AU - Marieka V. DeVuono AU - Tony Jung AU - Mar Rodríguez-Ruiz AU - Tsun Hay Jason Ng AU - Dana Gummerson AU - Emma Proud AU - Daniel B. Hardy AU - Ken K.-C. Yeung AU - Walter Rushlow AU - Steven R. Laviolette Y1 - 2022/09/01 UR - http://www.eneuro.org/content/9/5/ENEURO.0253-22.2022.abstract N2 - 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 (ECb) 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 (3 mg/kg) from gestational day (GD)7 until GD22. Anxiety-like, depressive-like, and reward-seeking behavior, 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 that 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 significant 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 (NAc). These findings identify several novel long-term risks of maternal cannabis use and demonstrate for the first time, sex-related effects of maternal cannabinoid exposure directly in the developing neural lipidome. ER -