Nerve cells have long processes called axons and dendrites which extend outward to form connections (synapses) with other nerve cells. Dr. Bassell’s team has developed powerful molecular genetic techniques to track mRNAs and FMRP particles as they move through these processes in brain tissue from Fragile X knockout mice. They have shown that a specific intracellular signaling pathway, the PI3K/mTOR pathway, is overactive in the absence of FMRP. This pathway is involved in mediating many neuronal neurotransmitter receptors. This project will test new drugs in development which inhibit an enzyme known as PI3 kinase, a part of the pathway, and have the potential to normalize neuronal function in Fragile X.

Animal models of the Fragile X syndrome (FXS) are characterized by excessive and dysregulated signaling through a number of neurotransmitter receptors. This suggests that the Fragile X protein (FMRP) might regulate a common downstream signaling molecule shared by multiple pathways. We and others have shown that a specific intracellular signaling pathway, the phosphoinositide-3 kinase (PI3K)/mTOR pathway, which mediates signaling downstream of many neuronal neurotransmitter receptors, is overactive in the absence of FMRP.

Our studies have shown that FMRP associates with and regulates the mRNA of p110ß, a catalytic subunit of PI3K, leading to excessive p110ß mRNA translation, protein expression and enzymatic function at synapses from Fmr1 KO mice (Gross et al., 2010). Additionally, we and others found that FMRP also associates with the mRNA encoding the PI3K enhancer PIKE, and that synaptic PIKE protein expression is increased in Fmr1 knockout mice. Taken together, these studies suggest that FMRP may play an important role in regulating and limiting signaling through the PI3K/mTOR pathway.

We thus hypothesize that pharmacologic treatments targeted at the PI3K/mTOR pathway might be a promising therapeutic strategy for patients with FXS. To further explore the PI3K/mTOR signaling complex as a therapeutic target in FXS, we are currently using genetic and pharmacologic rescue approaches to reduce the enzymatic function of specific components of this complex pathway in an FXS mouse model. Results from the first year of FRAXA funding suggest that these PI3K/mTOR pathway-specific rescue models for can reverse several FXS-associated neuronal dysfunctions, including cell-biological and behavioral phenotypes.

Specific drugs targeted at components of the PI3K/mTOR signaling pathway are being developed and used for cancer research. In this project, we are taking advantage of these advances in cancer research, by testing a specific p110ß-selective antagonist, which is currently used in a clinical trial with human cancer patients, for its potential to rescue or ameliorate FXS-associated phenotypes in the mouse model. We anticipate that in the future, PI3K/mTOR-targeted treatment strategies in patients with FXS could possibly benefit from drugs developed in cancer research.