Autism Centers of Excellence
Autism Spectrum Disorders (ASD) and intellectual disability are complex, multigenic disorders with significant heterogeneity due to the interaction of genetic, neurobiological, and environmental factors. While a number of factors may generate a common phenotype, the neurobiology of ASD and intellectual disability remains elusive. Several neural systems have been implicated; however, accumulating data support a role for neuronal connectivity in the pathogenesis of these disorders. A novel approach for neurodevelopmental disease research is to capitalize on breakthrough discoveries that are occurring in other disorders that share phenotypic characteristics with ASD and intellectual disabilities. Here, we propose to investigate the synaptic abnormalities in two Mendelian disorders highly associated with ASD and intellectual disabilities: Tuberous Sclerosis Complex (TSC) and Fragile X syndrome (FXS). We propose a set of experiments to investigate neuronal connectivity in mouse models of TSC and FXS. These experiments are based on our observations that TSC pathway components play an important role in regulating axonal wiring, and that neurons deficient in these proteins make aberrant axonal connections in the brain. Similarly, FXS mouse models have abnormalities in synaptic plasticity. By using dissociated cultures and brain sections, we will characterize the role of FMRP protein in axonal development focusing on the visual system. Complementary studies will be performed in Tsc-deficient mice to determine the role of the Tsc-mTOR pathway in visual cortical plasticity. By performing these studies in parallel in TSC and FXS models, we believe we can identify shared and distinct aspects of synaptic development and function that underlie neurological problems in these two diseases.
Our specific aims are:
1) To investigate axonal guidance in neurons from Fmr1 knockout mice, and
2) To compare functional and structural plasticity in primary visual cortex (V1) of FMRP- and TSC-deficient mice.
Our results may suggest further avenues of exploration to illuminate the complex causes of the devastating neurological symptoms that characterize ASD and intellectual disabilities, and may result in novel therapeutic options for our patients.