Grant: Project Grant

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disease manifested by deficits in social communication and interactions as well as repetitive behavior. It affects 1-2% of the global population, with a diagnosis four times higher in males. Individuals with ASD are at a heightened risk of developing psychiatric comorbidities. There is a need for novel approaches to treat ASD since 40% of affected children do not respond to the current available standard-of-care behavioral and medical treatments. Dysregulation of insulin signaling has been closely associated with ASD. The binding of insulin to its receptor (IR) on cells activates signaling pathways that trigger abnormal protein synthesis in monogenic forms of ASD. We discovered that IR is upregulated in postmortem brains and the Fragile X syndrome mouse model (FXS), an inherited genetic disorder characterized by mild-to-moderate intellectual disability and is also the most common inherited cause of ASD. However, the mechanism of increased insulin signaling in engendering abnormal phenotypes in FXS remains elusive. We posit that elevated levels of IR and its downstream signaling in the brain cause elevated protein synthesis and core ASD phenotypes in FXS mice and humans. By employing molecular genetics, we will decrease IR levels in male and female FXS mice to determine the potential reversal of elevated signaling pathways downstream of IR and the correction of impaired behavior and synaptic plasticity. We will investigate the impact of IR depletion on the mRNA and protein repertoire of FXS mice using Ribosome-Sequencing and proteomics, respectively. Finally, we will use a two-pronged treatment strategy involving antisense oligonucleotides and pharmacological agents to normalize dysregulated IR signaling and behavior abnormalities in FXS mice. This research aims to gain an understanding of FXS pathophysiology to find and design new treatment strategies for FXS and ASD.