RT Journal Article
SR Electronic
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
FD Society for Neuroscience
SP ENEURO.0253-22.2022
DO 10.1523/ENEURO.0253-22.2022
VO 9
IS 5
A1 Mohammed H. Sarikahya
A1 Samantha Cousineau
A1 Marta De Felice
A1 Kendrick Lee
A1 Karen KW Wong
A1 Marieka V. DeVuono
A1 Tony Jung
A1 Mar Rodríguez-Ruiz
A1 Tsun Hay Jason Ng
A1 Dana Gummerson
A1 Emma Proud
A1 Daniel B. Hardy
A1 Ken K.-C. Yeung
A1 Walter Rushlow
A1 Steven R. Laviolette
YR 2022
UL http://www.eneuro.org/content/9/5/ENEURO.0253-22.2022.abstract
AB 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.