Sex-dependent effects of in utero cannabinoid exposure on cortical function

• Published in: eLife 2018-09, Vol.7
• Main Authors: Bara, Anissa, Manduca, Antonia, Bernabeu, Axel, Borsoi, Milene, Serviado, Michela, Lassalle, Olivier, Murphy, Michelle, Wager-Miller, Jim, Mackie, Ken, Pelissier-Alicot, Anne-Laure, Trezza, Viviana, Manzoni, Olivier J
• Format: Article
• Language: English
• Subjects: Addictive behaviors; Allosteric properties; Allosteric Regulation - drug effects; Anandamide; Animal cognition; Animals; Anxiety; Anxiety - pathology; Arachidonic Acids - metabolism; Behavior; Behavior, Animal; Behavioral plasticity; Brain; Cannabinoids; Cannabinoids - pharmacology; Cannabis; Emotional behavior; Endocannabinoids - metabolism; Excitability; Female; Fetuses; Gender differences; Gene expression; Gene Expression Regulation, Developmental - drug effects; Genetic crosses; Gestation; Glutamic acid receptors (metabotropic); in-utero; Intrauterine exposure; Life Sciences; Long-term depression; Long-Term Potentiation - drug effects; Male; Marijuana; Memory; mRNA; Neuronal Plasticity - drug effects; Neurons and Cognition; Neuroscience; Nucleus Accumbens - drug effects; Nucleus Accumbens - pathology; Placenta; Polyunsaturated Alkamides - metabolism; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - pathology; Prefrontal Cortex - physiopathology; Pregnancy; Prenatal experience; Prenatal Exposure Delayed Effects - pathology; Prenatal Exposure Delayed Effects - physiopathology; Pyramidal cells; Pyramidal Cells - drug effects; Pyramidal Cells - metabolism; Rats, Wistar; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Metabotropic Glutamate 5 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sex Characteristics; sex difference; Social Behavior; Social interaction; Social Isolation; Software; Substance abuse treatment; Synaptic plasticity; TRPV Cation Channels - metabolism
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.36234

Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing reports of cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here, we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.