Prenatal Cannabidiol and THC Exposure Induce Sex-Specific Executive Dysfunction via Divergent Pathological Rewiring of the Adult Medial Prefrontal Cortex
Olivier J. J. Manzoni, Alba Cáceres-Rodríguez, Daniela Iezzi, Olivier Lassalle, Shuai Wang, Pascale Chavis
preprint DOI: 10.21203/rs.3.rs-9428628/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational animal study |
|---|---|
| Population | Adult (P100–140) mouse offspring exposed in utero to THC or CBD |
| Interventions | Cannabidiol (CBD) delta9-tetrahydrocannabinol (THC) |
| Dose | 3 mg/kg |
| Duration | Gestational days 5–18 exposure; offspring assessed at postnatal days 100–140 |
| Topics | Cannabis CBD |
| Key findings | Prenatal CBD and THC exposure in mice both increased repetitive behavior and abolished endocannabinoid-mediated long-term depression in medial prefrontal cortex neurons. CBD-exposed females uniquely showed impaired risk appraisal, while CBD-exposed males showed a bidirectional plasticity collapse. The authors argue that sex-specific circuit rewiring drives distinct executive dysfunctions and that prenatal CBD mirrors THC neurotoxicity. |
Abstract
Abstract Prenatal cannabidiol (CBD) consumption is rapidly increasing, driven by a perception of safety relative to delta9-tetrahydrocannabinol (THC). However, the long-term neurodevelopmental risks of gestational CBD remain largely uncharacterized. Using a sex-disaggregated framework, we investigated adult (P100–140) mouse offspring following in utero exposure (GD5–18; 3 mg/kg) to THC or CBD. Executive function was evaluated through risk-assessment and repetitive behavior tasks, coupled with targeted electrophysiological mapping of medial prefrontal cortex (mPFC) Layer 5 neurons, the primary hub for approach-avoidance arbitration. We found that prenatal cannabinoids induce divergent behavioral and physiological signatures. While increased repetitive behavior was a universal hallmark of exposure, impaired risk appraisal emerged uniquely in CBD-exposed females and was dissociated from classical anxiety. At the circuit level, THC and CBD remodeling converged on a universal ablation of endocannabinoid-mediated long-term depression (eCB-LTD). In males, CBD uniquely induced a state of synaptic rigidity: a bidirectional plasticity collapse underpinned by functional saturation, elevated AMPA/NMDA ratios, and slowed NMDAR activation kinetics. We suggest that this ceiling effect creates a top-down lock on the prefrontal output circuit, precluding the synaptic flexibility necessary for executive control. In contrast, females exhibited compound-specific reorganizations of E/I balance. CBD-exposed females developed a homeostatic scaled-up architecture that preserved net E/I balance but likely increased synaptic noise, whereas THC drove a pro-excitatory phenotype through the collapse of inhibitory control. In conclusion, prenatal CBD exposure mirrors THC neurotoxicity by hijacking sex-specific developmental trajectories. While the loss of eCB-LTD is a universal endophenotype, divergent molecular remodeling drives distinct executive failures. This study establishes that sex-specific circuit rewiring is the primary driver of adult dysfunction, providing a critical biological framework for clinical warnings against gestational CBD use.
Comparable studies
Other preclinical and animal studies on CBD, most cited first.
Citations in the library
Cites 3
- Cannabis and synaptic reprogramming of the developing brain. Nature Reviews Neuroscience July 2021
- Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone Nature Neuroscience September 11, 2019
- Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure. Molecular Psychiatry January 2017