Conditional deletion of neurexins dysregulates neurotransmission from dopamine neurons

  1. Charles Ducrot
  2. Gregory de Carvalho
  3. Benoit Delignat-Lavaud
  4. Constantin VL Delmas
  5. Priyabrata Halder
  6. Nicolas Giguère
  7. Consiglia Pacelli
  8. Sriparna Mukherjee
  9. Marie-Josée Bourque
  10. Martin Parent
  11. LuLu Y Chen  Is a corresponding author
  12. Louis-Eric Trudeau  Is a corresponding author
  1. Université de Montréal, Canada
  2. University of California, Irvine, United States
  3. University of Foggia, Italy
  4. Université Laval, Canada

Abstract

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which in addition to DA, glutamate or GABA are also released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. An emerging literature suggests that neuroligins, trans-synaptic cell adhesion molecules, regulate both DA connectivity and neurotransmission. However, the contribution of their major interaction partners, neurexins (Nrxns) is unexplored. Here we tested the hypothesis that Nrxns regulate DA neuron neurotransmission. Mice with conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) exhibited normal basic motor functions. However, they showed an impaired locomotor response to the psychostimulant amphetamine. In line with an alteration in DA neurotransmission, decreased levels of the membrane DA transporter (DAT) and increased levels of the vesicular monoamine transporter (VMAT2) were detected in the striatum of DAT::Nrxns KO mice, along with reduced activity-dependent DA release. Strikingly, electrophysiological recordings revealed an increase of GABA co-release from DA neuron axons in the striatum of these mice. Together, these findings suggest that Nrxns act as regulators of the functional connectivity of DA neurons.

Data availability

All primary data are provided in the source data files accompanying the manuscript.

Article and author information

Author details

  1. Charles Ducrot

    Department of Pharmacology and Physiology, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Gregory de Carvalho

    Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9179-7697
  3. Benoit Delignat-Lavaud

    Department of Pharmacology and Physiology, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Constantin VL Delmas

    Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Priyabrata Halder

    Department of Pharmacology and Physiology, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Nicolas Giguère

    Department of Pharmacology and Physiology, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Consiglia Pacelli

    Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4915-5823
  8. Sriparna Mukherjee

    Department of Pharmacology and Physiology, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Marie-Josée Bourque

    Department of Pharmacology and Physiology, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Martin Parent

    Department of Psychiatry and Neurosciences, Université Laval, Quebec City, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. LuLu Y Chen

    Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
    For correspondence
    chenly@uci.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8873-3481
  12. Louis-Eric Trudeau

    Department of Pharmacology and Physiology, Université de Montréal, Montreal, Canada
    For correspondence
    louis-eric.trudeau@umontreal.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4684-1377

Funding

Canadian Institutes of Health Research (MOP106556)

  • Louis-Eric Trudeau

University of California Irvine, School of Medicine (GF15247)

  • LuLu Y Chen

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

Ethics

Animal experimentation: All procedures involving animals and their care were conducted in accordance with the Guide to care and use of Experimental Animals of the Canadian Council on Animal Care. The experimental protocols (#21-113) were approved by the animal ethics committees of the Université de Montréal (CDEA).

Copyright

© 2023, Ducrot 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. Charles Ducrot
  2. Gregory de Carvalho
  3. Benoit Delignat-Lavaud
  4. Constantin VL Delmas
  5. Priyabrata Halder
  6. Nicolas Giguère
  7. Consiglia Pacelli
  8. Sriparna Mukherjee
  9. Marie-Josée Bourque
  10. Martin Parent
  11. LuLu Y Chen
  12. Louis-Eric Trudeau
(2023)
Conditional deletion of neurexins dysregulates neurotransmission from dopamine neurons
eLife 12:e87902.
https://doi.org/10.7554/eLife.87902

Share this article

https://doi.org/10.7554/eLife.87902

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