The Role of the New mTOR Complex, mTORC2, in Autism Spectrum Disorders
Technical Report,30 Sep 2013,29 Sep 2017
Baylor College of Medicine Houston United States
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The goal of my DOD-supported research is to determine the role of the new mTOR complexes mTORC1 and mTORC2 in Autism Spectrum Disorder ASD. Individuals with ASD exhibit impaired social interactions, repetitive abnormal repetitive behavior as well as cognitive problems. In addition, a large proportion of ASD individual suffer from seizures. Autism is a heritable genetically heterogeneous disorder and mutations in the negative regulator of the mammalian target of rapamycin mTOR signaling pathway PTEN were associated with ASD. However, little is known about the mechanism underlying Pten-induced pathology. Here, we show that in the hippocampus of pten fb-KO mice, where Pten is conditionally deleted in the murine forebrain, the activity of both mTORC1 and mTORC2 is increased. In addition, we found that pten fb-KO mice exhibit seizures, learning and memory and ASD-like behaviors. Interestingly, genetic dissection of mTORcomplexes function in vivo reveals that mTORC1 is responsible for the enlarged brain phenotype whereas mTORC2 regulates EEG seizures, learning and memory as well ASD-like phenotypes in pten-deficient mice. Moreover, we found that mTORC2 regulates these processes by controlling glucose metabolism. We also found that mTORC2, but not mTORC1, is crucially required for mGluR-LTD, a major form of synaptic plasticity involved mnemonic processes. Our new insights hold promise for new specific mTORC2-based treatments for ASD and related mTORopathies.
- Medicine and Medical Research
- Genetic Engineering and Molecular Biology