Grant: Project Grant

Despite the prevalence of neuropsychiatric disorders, the progress in understanding the pathophysiology and the development of effective therapies is very slow. Thus, the development of new therapies for Fragile-X Syndrome (FXS) and Autism Spectrum Disorders (ASD) is imperative. Dysregulation of translation has been documented in several mouse models of autism and FXS. Previous studies have focused on the mTOR and ERK pathways in mediating the aberrant translation in these disorders. An additional key signaling pathway controlling translation is the integrated stress response (ISR) pathway regulated via phosphorylation of the a subunit of eIF2. The function of ISR in the pathophysiology of autism has not been investigated. Our preliminary data indicate that eIF2a phosphorylation is reduced in the brain of Fmr1 KO mice and in other mouse models of autism. In the proposed project, we will examine the hypothesis that dysregulation of eIF2a-dependent translational control leads to an altered repertoire of proteins in the mouse model of Fragile X syndrome and conceivable other models of ASD, underlying abnormal synaptic function and behavioural deficits. A better understanding of the eIF2a phosphorylation-dependent translational control in autism might lead to the development of more targeted and efficient therapeutics for several forms of autism, where this pathway is dysregulated.