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

  1. Anissa Bara
  2. Antonia Manduca
  3. Axel Bernabeu
  4. Milene Borsoi
  5. Michela Serviado
  6. Olivier Lassalle
  7. Michelle N Murphy
  8. Jim Wager-Miller
  9. Ken Mackie
  10. Anne-Laure Pelissier-Alicot
  11. Viviana Trezza
  12. Olivier J Manzoni  Is a corresponding author
  1. Aix-Marseille University, INSERM, INMED, France
  2. University Roma Tre, Italy
  3. INSERM-Indiana University, United States

Abstract

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.

Data availability

The processed data for the qPCR, behavior and electrophysiological data generated during the course of our study have been provided as Source Data.

Article and author information

Author details

  1. Anissa Bara

    Aix-Marseille University, INSERM, INMED, Marseille, France
    Competing interests
    No competing interests declared.
  2. Antonia Manduca

    Aix-Marseille University, INSERM, INMED, Marseille, France
    Competing interests
    No competing interests declared.
  3. Axel Bernabeu

    Aix-Marseille University, INSERM, INMED, Marseille, France
    Competing interests
    No competing interests declared.
  4. Milene Borsoi

    Aix-Marseille University, INSERM, INMED, Marseille, France
    Competing interests
    No competing interests declared.
  5. Michela Serviado

    Section of Biomedical Sciences and Technologies, Department of Science, University Roma Tre, Rome, Italy
    Competing interests
    No competing interests declared.
  6. Olivier Lassalle

    Aix-Marseille University, INSERM, INMED, Marseille, France
    Competing interests
    No competing interests declared.
  7. Michelle N Murphy

    Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, INSERM-Indiana University, Bloomington, United States
    Competing interests
    No competing interests declared.
  8. Jim Wager-Miller

    Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, INSERM-Indiana University, Bloomington, United States
    Competing interests
    No competing interests declared.
  9. Ken Mackie

    Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, INSERM-Indiana University, Bloomington, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8501-6199
  10. Anne-Laure Pelissier-Alicot

    Aix-Marseille University, INSERM, INMED, Marseille, France
    Competing interests
    No competing interests declared.
  11. Viviana Trezza

    Section of Biomedical Sciences and Technologies, Department of Science, University Roma Tre, Rome, Italy
    Competing interests
    No competing interests declared.
  12. Olivier J Manzoni

    Aix-Marseille University, INSERM, INMED, Marseille, France
    For correspondence
    olivier.manzoni@inserm.fr
    Competing interests
    Olivier J Manzoni, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5579-6208

Funding

Institut National de la Santé et de la Recherche Médicale

  • Michela Serviado

Conselho Nacional de Desenvolvimento Científico e Tecnológico

  • Milene Borsoi

Agence Nationale de la Recherche (Cannado)

  • Anissa Bara
  • Anne-Laure Pelissier-Alicot
  • Olivier J Manzoni

Fondation pour la Recherche Médicale (Equipe FRM 2015)

  • Anissa Bara
  • Milene Borsoi
  • Olivier J Manzoni

National Institutes of Health (5R01DA043982-02)

  • Ken Mackie
  • Olivier J Manzoni

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animals were treated in compliance with the European Communities Council Directive (86/609/EEC) and the United States National Institutes of Health Guide for the care and use of laboratory animals.

Reviewing Editor

  1. Julie A Kauer, Brown University, United States

Publication history

  1. Received: February 26, 2018
  2. Accepted: August 15, 2018
  3. Accepted Manuscript published: September 11, 2018 (version 1)
  4. Version of Record published: September 28, 2018 (version 2)

Copyright

© 2018, Bara et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Anissa Bara
  2. Antonia Manduca
  3. Axel Bernabeu
  4. Milene Borsoi
  5. Michela Serviado
  6. Olivier Lassalle
  7. Michelle N Murphy
  8. Jim Wager-Miller
  9. Ken Mackie
  10. Anne-Laure Pelissier-Alicot
  11. Viviana Trezza
  12. Olivier J Manzoni
(2018)
Sex-dependent effects of in utero cannabinoid exposure on cortical function
eLife 7:e36234.
https://doi.org/10.7554/eLife.36234
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