Yue Feng, PhD, Principal Investigator (2004 to Present)
Wei Feng, PhD, FRAXA Postdoctoral Fellow (2011-2012)
Wenqi Li, PhD, Postdoctoral Fellow (2013)

FRAXA Awards:

by Wei Feng and Yue Feng, 5/1/2011

Fragile X Syndrome (FXS) patients suffer from a broad spectrum of cognitive dysfunction, including learning memory deficits, autistic behaviors, and social anxiety. Abnormalities in neuronal circuitry development and synaptic signaling due to the lack of FMRP-dependent translation regulation, represented by the aberrantly enhanced mGluR5, AKT/PI3K, GSK3, and mTOR signaling, are believed to underlie the mental impairment in FXS. The success in correcting several FXS abnormalities via modulating mGluR5 signaling provides a promising example for the treatment of FXS, which greatly encourages the efforts to develop additional therapeutic strategies by targeting other synaptic signaling pathways that are also affected in FXS.

Brain-derived neurotrophic factor (BDNF) and its receptors form a central signaling pathway that governs synaptic efficacy and long-term structural plasticity in the brain. Substantial functional overlaps between BDNF-TrkB signaling and FMRP pathway can be extracted from the literature. Moreover, emerging evidence suggests that TrkB signaling in Fmr1 KO mice may be impaired. The goal of our project is to determine whether the lack of FMRP results in abnormal production of proBDNF and/or mature BDNF in Fmr1 KO brains, which in turn leads to faulty signaling via the p75 receptor and/or TrkB receptor that exert opposing effects on synaptic strength. Moreover, we propose to test whether TrkB modulators can correct abnormalities in long-term neuronal structural plasticity and behavior in Fmr1 KO mice.

by Katie Clapp, 2/1/2011

by Yue Feng, 2/2/2005

We have a long-standing interest in understanding how FMRP controls translation of its mRNA targets, and how FMRP deficiency leads to misregulated protein production in fragile X syndrome. Our recent studies focus on brain development of the newborn Fmr1 KO mice; we have demonstrated the functional requirement of FMRP in repressing translation of MAP1B during the most active period of synapse development. We found that the lack of FMRP causes overproduction of MAP1B and aberrantly increased microtubule stability in brain neurons, which is a conceivable factor underlying the abnormal synapse development in the fragile X brain.

The goal of this project is to delineate the pathological consequence of misregulated MAP1B, as a result of lacking FMRP, in neuronal development as well as in epilepsy, and explore the possibility of correcting such abnormalities by manipulating MAP1B expression and microtubule dynamics in the fragile X neurons, by microtubule targeted drugs and ligands of neurotransmitter receptors. We believe these studies will provide important insights for identifying potential drug targets for the treatment of fragile X syndrome.