Conditional deletion of neurexins dysregulates neurotransmission from dopamine neurons
- Université de Montréal, Canada
- University of California, Irvine, United States
- University of Foggia, Italy
- 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
Gregory de Carvalho
Louis-Eric Trudeau
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).
Reviewing Editor
- Jun Ding, Stanford University, United States
Version history
- Preprint posted: October 17, 2021 (view preprint)
- Received: March 19, 2023
- Accepted: July 2, 2023
- Accepted Manuscript published: July 6, 2023 (version 1)
- Version of Record published: August 8, 2023 (version 2)
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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Conditional deletion of neurexins dysregulates neurotransmission from dopamine neurons
eLife 12:e87902.
https://doi.org/10.7554/eLife.87902
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