Regulation of mTOR signaling in the developing cerebral cortex as a point of convergence for multiple autism risk factors

PROJECT SUMMARY/ABSTRACT Signaling through mTOR is a critical regulator of protein synthesis in the developing brain, and numerous autism spectrum disorder (ASD) and intellectual disability (ID) risk genes have been identified that impinge on mTOR signaling and cause altered growth and connectivity at the level of brain areas/circuits or individual cell types. Mutations in dual-specificity tyrosine phosphorylation-regulated kinase 1a (DYRK1A) cause microcephaly and neuronal undergrowth in a subset of individuals with ASD and ID, as well as in mouse models. The mechanisms by which mutations in DYRK1A lead to microcephaly and ASD/ID are unknown but are critical to identify for the development of targeted treatments. Given the observations that multiple ASD risk genes that impact overall brain growth exhibit altered mTOR signaling and that decreased mTOR signaling in the developing cerebral cortex has been linked with microcephaly, pyramidal neuron undergrowth and deficits in behavior and cognition, we are testing the hypothesis that DYRK1A mutations cause microcephaly, neuronal undergrowth and ASD-relevant behavioral deficits through dysregulated mTOR signaling. Preliminary data collected during the previous funding period indicate that mTOR signaling is downregulated in the developing cerebral cortex of Dyrk1a mutant mice, and that upregulation of mTOR signaling via genetic suppression of Pten or pharmacological treatment with IGF-1 can rescue microcephaly and neuronal undergrowth in this model. The two aims of this proposal are designed to: 1) profile the effects of cerebral cortical Dyrk1a mutations on neuroanatomical and behavioral phenotypes relevant to the DYRK1A clinical population and to dysregulated mTOR signaling, and 2) test the hypothesis that Dyrk1a and mTOR signaling act in a common regulatory network to influence ASD-relevant brain growth and behavioral phenotypes. Completion of this project will elucidate molecular and cellular mechanisms of microcephaly, neuronal undergrowth and ASD-relevant behavioral deficits caused by mutations in DYRK1A and other ASD/ID risk genes that impinge on the mTOR pathway and will guide the development of treatments for the DYRK1A clinical population.