| The organization of local microcircuits in the neocortex is the basis of cortical computation. I began my thesis work characterizing the organization of excitatory microcircuits of corticostriatal and corticospinal projection neurons in the motor cortex. I found that circuits of these pyramidal neurons were specified not only by their long- range axonal targets or their laminar positions, but by both, in specific combinations. With this knowledge, I turned my focus to a newly developed conditional knockout mouse with implications for autism spectrum disorder (ASD). ASD is thought to be a disorder of cortical connectivity, one in which local cortical microcircuits are hyperconnected. This complex developmental disorder is characterized by social deficits, language impairment, and restricted interests. Its high heritability indicates a genetic component, but the genes involved remain elusive. Genetic linkage techniques recently revealed that individuals with ASD are three times more likely to have a mutation in the promoter region of the gene for mesenchymal-epithelial transition factor (MET) receptor tyrosine kinase (hereafter MET), which results in reduced MET expression. The MET signaling pathway is important for the normal development of the cerebral cortex. I used a mouse model of MET-deficiency to measure the local cortical connectivity of corticostriatal and corticopontine projection neurons. My results showed that the loss of MET lead to hyperconnectivity in specific local cortical circuits and provided a neurobiological substrate for MET-mediated ASD risk. |
