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Interagency Autism Coordinating Committee (IACC)
Autism Research Database
Office of Autism Research Coordination (OARC)
 
Project Element Element Description

Project Title

Project Title

TSC/mTOR Signaling in Adult Hippocampal Neurogenesis: Impact on Treatment and Behavioral Models of Autism Spectrum Disorders in Mice

Principal Investigator

Principal Investigator

Sano, Yoshitake

Description

Description

Autism spectrum disorders ASD) form a heterogeneous neurodevelopmental syndrome characterized by deficits in social interactions, language development and repetitive behavior/restricted interests. Although their pathology and neurobiological etiology have not been unified yet, ASD is observed in some genetic syndromes such as Fragile X, Rett syndrome, tuberous sclerosis TSC), etc. TSC2, a causal gene for TSC, is an important susceptibility gene for ASD. In people who have TSC insufficiency, there is a drastic increase in ASD 20-60% of TSC cases also have ASD). We reported that an interaction between high seasonal flu activity in late gestation and TSC mutations is observed in ASD patients, and also experimentally showed that Tsc2 haploinsufficiency and gestational immune activation cooperate to disrupt social interaction behavior in adult mice. Insufficiency of Tsc2 results in hyperactivation of mammalian target of rapamycin mTOR) signaling. Altered TSC/mTOR-related cell signaling is emerging as a feature common to a subset of ASD. Beyond TSC2, there are a number of other autism susceptibility genes, including NF1 causal gene for Neurofibromatosis type I), FMR1 causal gene for Fragile X syndrome), DISC1 Disrupted-in-schizophrenia 1; genetic risk factor for schizophrenia), PTEN, eIF4E, etc., that are also thought to alter mTOR dependent translation/signaling. There is a lot of evidence indicating that ASD are caused by changes in developmental processes that disrupt brain function. In addition, there is growing evidence that changes specific to the adult brain may contribute to ASD. Recently, we found that decreasing Disc1 levels in adult newborn neurons of DG which is one of the few regions of the adult brain where new neurons are continuously generated, caused cognitive and affective deficits relate to psychiatric disorders. And these abnormalities were reversed by treatment of rapamycin which is inhibitor of mTOR signaling. These results indicate that the dysregulation of mTOR signaling in adult newborn neurons is sufficient to cause abnormalities in ongoing neurodevelopmental processes and behaviors, which could be one of the underlying mechanisms contributing to the endophenotypes of psychiatric disorders such as ASD and schizophrenia. Here, we propose to extend these studies with the specific aims of determining 1) whether Tsc2 haploinsufficiency mice show abnormal adult neurogenesis in DG. 2) We also propose to determine whether increased mTOR signaling caused by disruption of Tsc2 in adult newborn DG neurons results in ASD related phenotypes. 3) Importantly, we propose to test whether an FDA approved mTOR inhibitor rapamycin) that is in clinical trial with TSC, reverses the behavioral abnormalities caused by Tsc2 down-regulation in adult newborn neurons of DG. The proposed studies will reveal whether certain aspects of ASD endophenotypes are, at least in part, caused by the abnormalities in adult neurogenesis, which can be also reversed in the adult stage. The results showing that there are adult components of pathophysiology for ASD beyond the neurodevelopmental stages could provide the many millions of people affected with ASD a new hope for the treatment even in adult.

Funder

Funder

Brain & Behavior Research Foundation

Fiscal Year Funding

Fiscal Year Funding

7769

Current Award Period

Current Award Period

2014-2016

Strategic Plan Question

Strategic Plan Question

Question 2: How Can I Understand What Is Happening?

Strategic Plan Objective

Strategic Plan Objective

2O. Not specific to Question 2 objectives

Project Link

Project Link

No link available.

Institution

Institution

University of California, Los Angeles

State/Country

State/Country

California

Project Number

Project Number

Federal or Private?

Federal or Private?

Private

Received ARRA Funding?

Received ARRA Funding?

No

History/Related Projects

History/Related Projects

TSC/mTOR Signaling in Adult Hippocampal Neurogenesis: Impact on Treatment and Behavioral Models of Autism Spectrum Disorders in Mice | 0 | 2014 |

 
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