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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

A cerebellar mutant for investigating mechanisms of autism in Tuberous Sclerosis

Principal Investigator

Principal Investigator

Sahin, Mustafa

Description

Description

Currently there are no approved drugs that treat the core symptoms of autism, creating a huge unmet need for the millions of individuals around the world affected with this condition. One approach for identifying drugs for the core features of autism is to use validated animal models that mimic these features in behavioral paradigms. Such models can be essential tools for testing hypotheses and developing novel treatments. A genetic disease associated with a high risk of developing autism spectrum disorders is tuberous sclerosis complex (TSC). This disease occurs due to mutations in the TSC1 or TSC2 genes, which are evolutionarily well conserved. In mice these genes are called Tsc1 and Tsc2, respectively. These two genes normally put a brake on protein synthesis in cells and prevent overgrowth. When they are mutated, they result in the presence of enlarged cells and exuberant neuronal connections. Aberrant protein synthesis appears to be a mechanism involved in not only TSC, but also a number of other genetic autism syndromes. The investigators have generated a new mouse model by deleting the Tsc1 gene only in a subset of cells in the cerebellum. The cerebellum is a part of the brain that has been implicated in autism based on human studies, but mouse models that rigorously demonstrate a role for the cerebellar dysfunction leading to core features of autism are lacking. Their Tsc1 cerebellar knockout mice avoid social interactions with other animals and new social situations, similar to people with autism including difficulty in a "reversal learning" task, suggesting their restrictive/repetitive interests. Importantly, treating these mice with a small molecule (rapamycin) in early life prevents the development of these symptoms. The overall goal of this study is to understand how loss of Tsc1 function in the cerebellum leads to autism-like traits in mice. First, the study examines how the brain is wired in these mice. This will provide important insights about the brain circuits that contribute to autistic symptoms. Since these symptoms are preventable by rapamycin treatment, this mouse model provides an unprecedented opportunity to ask whether critical periods exist for development and treatment of autism-like traits in mice. Given that aberrant protein synthesis may be a common mechanism shared by several genetic causes of autism, findings from this mouse model may have important implications for other types of autism as well.

Funder

Funder

Autism Speaks

Fiscal Year Funding

Fiscal Year Funding

0

Current Award Period

Current Award Period

2011-2014

Strategic Plan Question

Strategic Plan Question

Question 2: How Can I Understand What Is Happening?

Strategic Plan Objective

Strategic Plan Objective

Green dot: Objective has greater than or equal to the recommended funding. 2SD. Launch three studies that target improved understanding of the underlying biological pathways of genetic conditions related to autism (e.g. Fragile X, Rett syndrome, tuberous sclerosis complex) and how these conditions inform risk assessment and individualized intervention by 2012. IACC Recommended Budget: $9,000,000 over 5 years.

Project Link

Project Link

A cerebellar mutant for investigating mechanisms of autism in Tuberous Sclerosis (External web link)

Institution

Institution

Boston Children's Hospital

State/Country

State/Country

Massachusetts

Project Number

Project Number

7665

Federal or Private?

Federal or Private?

Private

Received ARRA Funding?

Received ARRA Funding?

No

History/Related Projects

History/Related Projects

A cerebellar mutant for investigating mechanisms of autism in Tuberous Sclerosis | 0 | 2011 | 7665
A cerebellar mutant for investigating mechanisms of autism in Tuberous Sclerosis | 149958 | 2012 | 7665
A cerebellar mutant for investigating mechanisms of autism in Tuberous Sclerosis | 149937 | 2014 | 7665
A cerebellar mutant for investigating mechanisms of autism in Tuberous Sclerosis | 149967 | 2013 | 7665

 
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