p.T8I-VGLUT3 variant as a marker of vulnerability to stress in mice

Environmental stress plays a key role in the development of psychiatric disorders, and also has a negative impact on sleep integrity. Insomnia and sleep disturbances are core symptoms observed in patients with stress-related disorders. However, stress reactivity is the result of a combination of genetic and environmental influences that ultimately impacts one’s physiology and behavior in a variety of ways. In this project we will focus on stress susceptibility and how it could trigger psychiatric diseases in a peculiar gene-environment interaction.Studying glutamatergic neurotransmission, we discovered that a peculiar transporter (VGLUT3) is associated to stress-related brain disorders including anxiety, depression and addiction. Working with psychiatric in patients with severe addiction, we identified an over-represented mutation -p.T8I- in the gene encoding VGLUT3 (SLC17A8).Our central working hypothesis is that the p.T8I mutation alters the properties of VGLUT3 with consequences on the homeostatic state that could trigger stress-related psychiatric diseases.Our study assessed VGLUT3T8I/T8I mice sociability, and anxiety phenotypes as well as sleep-wake patterns in conditions either exempt of environmental stress or after a chronic social defeat stress.We found that VGLUT3T8I/T8I mice are more susceptible to stress in a sex dependent manner. Moreover we studied the mechanisms underlying their vulnerability focusing on the ventral striatum and using fiber photometry to follow cholinergic and dopaminergic transmission.Our results confirmed the role of the p.T8I mutation in susceptibility to stress.