The Role of the New mTOR Complex, mTORC2, in Autism Spectrum Disorders
Abstract
The goal of my DOD-supported research is determine the role of the new mTOR complex (mTORC2) in Autism Spectrum Disorder (ASD). ASD individuals exhibit impaired social interactions, seizures and abnormal repetitive behavior. In addition, 70-80% of autistic individuals suffer from mental retardation. Autism is a heritable genetically heterogeneous disorder and mutations in negative regulators of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, such as PTEN were associated with ASD. 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, Pten fb-KO mice exhibit seizures, learning and memory, stereotype/repetitive behaviors and social deficits. Our remarkable preliminary data show that genetic inhibition of mTORC2, but not mTORC1, in Pten-deficient mice significantly promotes survival and seizures. In addition, Pten-rictor fb- double KO (DKO) mice, in which mTORC2 activity is restored to normal levels, EEG seizures, learning and memory as well as social phenotypes, are all rescued. We also found that in Pten-deficient mice mitochondria respiration is impaired and mTORC2 silencing restores mitochondria dynamics. In the third, year we will investigate the mechanism by which mTORC2 regulates mitochondria respiration. In addition, we will assess metabolic changes in neurons lacking Pten. These insights hold the promise for new mTORC2-based treatment of ASD.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1001594
Entities
People
- Mauro Costa-Mattioli
Organizations
- Baylor College of Medicine