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

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.T81 variant. In VGLUT3^T8I/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 VGLUT3^T8I/T8I male mice. Our study suggests that unbalanced dopaminergic transmission in the dorsal striatum could be a common mechanism between SUDs and EDs.

Mathieu Favier, Elena Martin Garcia, Romain Icick, Camille de 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, Salah El Mestikawy