Dysregulation of mTOR Signaling in Fragile X Syndrome

DESCRIPTION (provided by applicant): Fragile X syndrome is the most common heritable disorder of intellectual disabilities and a leading genetic cause of autism. The onset of symptoms occurs by the age of 3, and usually requires extensive support for the lifetime of the afflicted. An estimated one in every 3000 children born in the U.S. develops Fragile X syndrome. An effective treatment for the cognitive and social interaction deficits associated with Fragile X remains an unmet medical need. The mammalian target of rapamycin (mTOR) pathway is a central regulator of cell growth, proliferation and cap-dependent protein translation. Our recent discovery that mTOR signaling is over activated in a mouse model of Fragile X and is causally related to impaired synaptic plasticity implicates dysregulation of the mTOR pathway in the etiology of intellectual disabilities. Our recent finding in collaboration with Eric Klann that mTOR signaling is over activated in humans with Fragile X underscores the clinical relevance of the proposed research. Our finding that PI3 Kinase Enhancer (PIKE), an upstream activator of mTOR and identified target of Fragile X Mental Retardation Protein (FMRP), is elevated in Fragile X mice provides a functional link between FMRP and mTOR signaling. The overall goals of the proposed research are to characterize deficits in signaling, spine dynamics, synaptic plasticity and cognition in a mouse model of Fragile X syndrome and to identify novel therapeutic strategies for amelioration of this debilitating human condition. The underlying hypothesis is that silencing of FMRP leads to elevated PIKE and over activated mTOR signaling, which are causally related to spine abnormalities, impaired synaptic plasticity, cognition and social interactions in Fragile X syndrome. Specific Aims are: Aim 1. Examine a causal relation between the gene known to cause Fragile X syndrome and impaired mTOR signaling, spine morphogenesis, synaptic plasticity, cognition and autistic behaviors in adult mice. As an alternative strategy we will use a floxed Fmr1 mouse to examine the ability of conditional knockdown of Fmr1 to induce over activated mTOR signaling and recapitulate the Fragile X phenotype in adult mice. Aim 2. Examine a causal relation between elevated PIKE, over activated mTOR signaling and the Fragile X phenotype. Aim 3. As a complementary strategy, we will document a causal relation between dysregulation of mTOR signaling and the Fragile X phenotype. In addition, we will examine the ability of drugs that target mTOR to ameliorate neurologic deficits. To undertake this research initiative, we have attracted stellar scientific collaborators. Bernardo Sabatini, Harvard Medical School, a world-renowned synaptic physiologist, will perform spine imaging experiments. Synaptic plasticity and behavioral experiments will be performed in collaboration with Eric Klann, New York University, an expert in the fields of synaptic physiology and autism. Jacqueline Crawley, NIMH, a world-renowned expert in behavioral analysis of mouse models of autism will serve as a Behavioral Advisor. It is hoped that this in-depth analysis of synaptic and circuitry defects in a mouse model of Fragile X will improve the diagnosis, treatment, and prevention of this human condition. Findings from these studies will accelerate the discovery of novel therapeutic strategies with broad potential not only for Fragile X syndrome, but other developmental disorders. PUBLIC HEALTH RELEVANCE: Fragile X syndrome is the most common heritable disorder of mental retardation and a leading form of autism. Fragile X syndrome exhibits ~30% co-occurrence with autism. The onset of symptoms occurs by the age of 3, and usually requires extensive support for the lifetime of the afflicted. An estimated one in every 3000 children born in the U.S. develops Fragile X syndrome. An effective treatment for the cognitive and social interaction deficits associated with Fragile X remains an unmet medical need. The proposed research will examine the ability of therapeutic strategies targeting mTOR signaling to rescue impaired synaptic plasticity and behavior in adult Fmr1 KO mice. These translational studies will create a foundation for generating novel therapeutic strategies to ameliorate this serious human condition.