Project Detail
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Aberrant synaptic form and function due to TSC-mTOR-related mutation in autism spectrum disorders  

Many children with autism have unusually high numbers of synapses, or connections between neurons, particularly in the cortex, which may result from overgrowth and a disruption of neuronal pruning during childhood. Pruning and reshaping of neurons pares down the number of synapses in the brain while eliminating inappropriate synapses that lead to over-connectivity between brain regions, and possibly inappropriate learning, behavior and seizures. David Sulzer and his colleagues at Columbia University hypothesize that autism-associated mutations in the tuberous sclerosis gene, TSC, can cause overconnectivity when the target of TSC, the mTOR pathway, interferes with normal neuronal pruning. Neuronal pruning largely occurs by the cell's breakdown of internal components, a process called macroautophagy. The mTOR pathway turns off macroautophagy, but macroautophagy can proceed upon inhibition of mTOR by TSC proteins. The researchers hypothesize that autism-linked mutations in TSC deregulate mTOR, allowing the pathway to inhibit macroautophagy in neurons, which could then lead to neuronal overgrowth and over-connectivity. To test this hypothesis, the researchers are studying macroautophagy in the synapses of mice deficient of TSC, which should deregulate mTOR, and of mice deficient of macroautophagy genes, which should also prevent pruning. They plan to examine brain structures for atypical pruning or neuronal overgrowth in these mice. They also plan to use these mice to determine whether deregulation of mTOR results in abnormal increases in cortical synapses and neuronal activity. In parallel, the researchers also plan to investigate whether the brains of individuals with autism show changes in synapses consistent with the effects detected in the mutant mice. The researchers further propose to test whether rapamycin, a drug that inhibits the mTOR protein, could compensate for the loss of the TSC proteins in mice. If rapamycin can restore normal levels of macroautophagy and synaptic pruning in TSC-deficient mice, perhaps a similar drug would be beneficial in individuals with autism who have mutations in the mTOR-related pathways. Project Status


Funder Simons Foundation
Fiscal Year Funding $150,000.00
Current Award Period 2010-2013
Project Number 177936
Principal Investigator Sulzer, David
Received ARRA Funding? No
Strategic Plan Question Question 2: How Can I Understand What Is Happening? (Biology)
Subcategory Molecular Pathways
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.
Federal or Private? Private
Institution Columbia University
State/Country New York
Web Link 1 Aberrant synaptic form and function due to TSC-mTOR-related mutation in autism spectrum disorders (External web link)
Web Link 2 No URL available.
Web Link 3 No URL available.
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