Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders with symptoms that include deficits in social interaction, impaired communication skills, and repetitive behaviors. Mutations in hundreds of genes are associated with ASDs. It is essential to find the common pathophysiology induced by these mutations in order to develop an effective therapeutic strategy for ASDs. One common biochemical pathway underlying ASDs is dysregulation of synaptic protein synthesis control. However, it remains to be determined which neural circuits generate autistic-like behaviors when they are altered due to exaggerated protein synthesis. This knowledge would be critical for understanding the autistic pathophysiology and for developing novel therapeutic interventions for ASDs. In order to identify the diseased neural circuits behind autistic symptoms, we have generated a knock-in mouse strain (TB-Eif4e-KI) in which eIF4E is overexpressed from the Rosa26 locus in a Cre-dependent manner. We posit that eIF4E overexpression in neurons will lead to autistic-like behaviors in mice. To this end, we will employ the Cre transgene under the control of the promoter for synapsin (Syn-Cre). Because it has not been tested that autistic behaviors are not due to exaggerated protein translation in glial cells, we will also employ the Cre transgene driven by the promoter for glial fibriliary acidic protein (GFAP-CreERT2) to overexpress eIF4E in astrocytes. If this exploratory research project demonstrates that our hypothesis is correct, we will identify the neural circuits that produce autistic-like behaviors by overexpressing eIF4E in specific neuronal groups and brain areas using Cre transgenes and Cre- expressing virus in the future studies.
ASDs are a heterogeneous group of heritable neurodevelopmental disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and repetitive behaviors or restricted interests. This research project is aimed to identify specific neural circuits that trigger these behaviors. Pharmacological manipulation of the activity of these neural circuits could be an effective way to treat ASDs.
