The human VGLUT3-pT8I mutation elicits uneven striatal DA signaling, food or drug maladaptive consumption in male mice

Mathieu Favier (), Elena Martin Garcia, Romain Icick, Camille Almeida, Joachim Jehl, Mazarine Desplanque, Johannes Zimmermann, Annabelle Henrion, Nina Mansouri-Guilani, Coline Mounier, Svethna Ribeiro, Fiona Henderson, Andrea Geoffroy, Sebastien Mella, Odile Poirel, Véronique Bernard, Véronique Fabre, Yulong Li, Christian Rosenmund, Stéphane Jamain, Florence Vorspan, Alexandre Mourot, Philibert Duriez, Leora Pinhas, Rafael Maldonado, Nicolas Pietrancosta, Stéphanie Daumas and Salah El Mestikawy ()
Additional contact information
Mathieu Favier: McGill University
Elena Martin Garcia: Universitat Pompeu Fabra (UPF)
Romain Icick: Assistance Publique - Hôpitaux de Paris (AP-HP)
Camille Almeida: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Joachim Jehl: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Mazarine Desplanque: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Johannes Zimmermann: Institut für Neurophysiologie
Annabelle Henrion: Fondation FondaMental
Nina Mansouri-Guilani: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Coline Mounier: McGill University
Svethna Ribeiro: McGill University
Fiona Henderson: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Andrea Geoffroy: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Sebastien Mella: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Odile Poirel: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Véronique Bernard: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Véronique Fabre: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Yulong Li: Peking University School of Life Sciences
Christian Rosenmund: Institut für Neurophysiologie
Stéphane Jamain: Fondation FondaMental
Florence Vorspan: Assistance Publique - Hôpitaux de Paris (AP-HP)
Alexandre Mourot: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Philibert Duriez: Institute of Psychiatry and Neuroscience of Paris (INSERM UMR1266)
Leora Pinhas: PHLIP Mental Health and Painless Medicine clinic
Rafael Maldonado: Universitat Pompeu Fabra (UPF)
Nicolas Pietrancosta: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Stéphanie Daumas: Neuroscience Paris Seine – Institut de Biologie Paris Seine (NPS – IBPS)
Salah El Mestikawy: McGill University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Cholinergic striatal interneurons (ChIs) express the vesicular glutamate transporter 3 (VGLUT3) which allows them to regulate the striatal network with glutamate and acetylcholine (ACh). In addition, VGLUT3-dependent glutamate increases ACh vesicular stores through vesicular synergy. A missense polymorphism, VGLUT3-p.T8I, was identified in patients with substance use disorders (SUDs) and eating disorders (EDs). A mouse line was generated to understand the neurochemical and behavioral impact of the p.T8I variant. In VGLUT3T8I/T8I male mice, glutamate signaling was unchanged but vesicular synergy and ACh release were blunted. Mutant male mice exhibited a reduced DA release in the dorsomedial striatum but not in the dorsolateral striatum, facilitating habit formation and exacerbating maladaptive use of drug or food. Increasing ACh tone with donepezil reversed the self-starvation phenotype observed in VGLUT3T8I/T8I male mice. Our study suggests that unbalanced dopaminergic transmission in the dorsal striatum could be a common mechanism between SUDs and EDs.

Date: 2024
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DOI: 10.1038/s41467-024-49371-1

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