Exploring deficits in lineage-dependent neocortical circuit assembly in a mouse model of fragile X syndrome

Despite the fact that autism spectrum disorders (ASDs) are considered neurodevelopmental disorders, the precise links between early brain development abnormalities and later functional deficits remain largely unknown. Song-Hai Shi proposes that deficits in lineage-dependent progressive assembly of precise local and long-range cortical neuronal circuits during development underlie the impairments in the cortex of individuals with ASDs. Shi plans to test this hypothesis in a mouse model of fragile X syndrome, which lacks the Fmr1 gene.

Specifically, Shi will 1) characterize the production and spatial organization of clonally related cortical excitatory neurons arising from individual radial glial progenitor cells lacking Fmr1; 2) investigate local microcircuit assembly of clonally related cortical excitatory neurons lacking Fmr1; and 3) determine long-range top-down circuit assembly of clonally related cortical excitatory neurons lacking Fmr1.

This project integrates a battery of cutting-edge approaches to investigate lineage-dependent, precise, local and long-range circuit assembly in a mouse model of fragile X syndrome. The tools and assays established here can be readily applied to other animal models to test the prevalence of lineage-dependent circuitry deficits in ASDs. This project will not only provide fundamental new insights into neuronal circuit defects in ASDs, but also shed light on the pathophysiology of early developmental abnormalities in ASDs.