Study of the VGLUT3-pT8I mutation unravels common mechanisms of drug and food misuse and suggests potential treatment for eating disorder

Cholinergic striatal interneurons (ChIs) express the vesicular glutamate transporter 3 (VGLUT3) allowing them to regulate the striatal network not only with acetylcholine (ACh), but also with glutamate. Moreover, VGLUT3-dependent glutamate increases ACh vesicular stores through a mechanism named vesicular synergy (Gras et al, 2008). A few years ago, we identified a missense polymorphism, VGLUT3-p.T8I, in patients with substance use disorders (SUDs) and eating disorders (EDs) (Sakae et al 2015). We generated a mouse line carrying the p.T8I variant to understand the neurochemical and behavioral impact of it. Surprisingly, we observed no glutamate signaling modification however vesicular synergy and ACh release were blunted resulting in  dopamine release modifications in the striatum. Behavioral studies showed that mutant mice exhibited a facilitation of habit formation and an exacerbation of maladaptive use of drug or food, that could be reversed by increasing ACh tone with donepezil. Our work suggests that unbalanced dopaminergic transmission in the striatum could be a common mechanism between substance use and eating disorders and advocates for the use of donepezil to treat these pathologies.

Stéphanie Daumas est invitée par Sébastien Carnicella.