Reducing obesity in Autism Spectrum Disorders – striatal RGS4 as a novel therapeutic target

Overweight and obesity are frequently reported in individuals with fragile X syndrome (FXS), a single-gene cause of autism spectrum disorders (ASD). Imbalances within circuits of the striatum are implicated in the overeating process.

The loss of the fragile X mental retardation protein (FMRP) results in dysregulated de novo translation in neurons and reduced expression of RGS4, an enzyme implicated in plasticity mechanisms of striatal medium spiny neurons (MSNs).

The goal of this project is to investigate whether overeating in FXS originates from dysregulated de novo translation of specific mRNA pools in the two populations of MSNs, which results in changes in cortico-striatal synaptic plasticity and function.

The project includes three specific aims:AIM 1: To determine whether FMRP differentially alters de novo translation into the two subpopulations of striatal medium spiny neurons, and modulates distinct mRNA pools.AIM 2: To identify potential alterations in spine density and synaptic functions in the striatal medium spiny neurons of the fragile X syndrome mouse model.AIM 3: To test the modulation of RGS4 activity as a therapeutic approach for controlling feeding behavior and reducing overweight / obesity on fragile X syndrome mouse model.The work plan includes state-of-the-art techniques based on neuropharmacology, electrophysiology, and behavioral analysis.

The urgent need for an efficacious therapy for reducing overeating in ASD underlies the importance of my project.