Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes towards it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase of dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related-behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.HighlightsPCE female offspring do not manifest a disease-relevant phenotypePrenatal THC does not affect female dopaminergic neuronsPCE female mesolimbic dopamine function is less responsive to acute THC

IntroductionFragile X syndrome (FXS), resulting from a mutation in the Fmr1 gene, is the most common monogenic cause of autism and inherited intellectual disability. Fmr1 encodes the Fragile X Messenger Ribonucleoprotein (FMRP), and its absence leads to cognitive, emotional, and social deficits compatible with the nucleus accumbens (NAc) dysfunction. This structure is pivotal in social behavior control, consisting mainly of spiny projection neurons (SPNs), distinguished by dopamine D1 or D2 receptor expression, connectivity, and associated behavioral functions. This study aims to examine how FMRP absence differentially affects SPN cellular properties, which is crucial for categorizing FXS cellular endophenotypes.MethodsWe utilized a novel Fmr1−/y::Drd1a-tdTomato mouse model, which allows in-situ identification of SPN subtypes in FXS mice. Using RNA-sequencing, RNAScope and ex-vivo patch-clamp in adult male mice NAc, we comprehensively compared the intrinsic passive and active properties of SPN subtypes.ResultsFmr1 transcripts and their gene product, FMRP, were found in both SPNs subtypes, indicating potential cell-specific functions for Fmr1. The study found that the distinguishing membrane properties and action potential kinetics typically separating D1- from D2-SPNs in wild-type mice were either reversed or abolished in Fmr1−/y::Drd1a-tdTomato mice. Interestingly, multivariate analysis highlighted the compound effects of Fmr1 ablation by disclosing how the phenotypic traits distinguishing each cell type in wild-type mice were altered in FXS.DiscussionOur results suggest that the absence of FMRP disrupts the standard dichotomy characterizing NAc D1- and D2-SPNs, resulting in a homogenous phenotype. This shift in cellular properties could potentially underpin select aspects of the pathology observed in FXS. Therefore, understanding the nuanced effects of FMRP absence on SPN subtypes can offer valuable insights into the pathophysiology of FXS, opening avenues for potential therapeutic strategies.