Julius Zhu, PhD—University of Virginia
Serotonergic rescue of synaptic plasticity in FMR1 knockout mice

Julius Zhu, PhD, Principal Investigator
Chae-Seok Lim, PhD, FRAXA Postdoctoral Fellow

FRAXA Awards:

$9,978 in 2012
$52,898 in 2011
$50,000 in 2010
$50,000 in 2009
$65,000 in 2004
$44,000 in 2003


Dr. Zhu, a professor of pharmacology, is examining the effects of a number of drugs (some in common use already in fragile X, such as Buspar and Abilify) which manipulate specific serotonin receptors and the effect that these have on synaptic plasticity (LTP and LTD).
Update: Serotonergic rescue of synaptic plasticity in FMR1 knockout mice

This project was first funded in 2010 and renewed in 2011.

by Julius Zhu, 4/5/2011

We have recently demonstrated that: 1) aberrant Ras-PI3K-PKB/AKT signaling is responsible for the impaired synaptic delivery of GluA1 during LTP in FMR1 knockout mice (mice bred to mimic the human fragile X syndrome) and; 2) enhancing postsynaptic Ras-PI3K-PKB signaling restores normal LTP in these mice.  These findings explain the observation that FMR1 knockout mice are behaviorally similar to GluA1 knockout mice.

Due to the lengthy and expensive drug discovery process (i.e., ~8-15 years and ~800-1,800 million dollars per drug), any effective treatment for fragile X seems still years away.  As an alternative approach, we plan to investigate the clinical puzzles why certain psychoactive drugs (e.g., Nefazodone, Aripiprazole, Buspirone and Adderall) have moderately beneficial effects on cognitive performance of fragile X patients and why their effectiveness seems dependent on the receptor subtype pharmacology and dosage.  The project is also designed to test the hypothesis that properly combined and dosed psychoactive drugs may synergistically restore the normal GluA1-dependent synaptic plasticity in FMR1 knockout mice.  The findings of this project will suggest that cocktails of properly dosed FDA-approved drugs may be used as effective and immediately accessible treatments for fragile X.
FMRP Regulates Small GTPase Ras Signaling and Glutamate Receptor Trafficking

By Katie Clapp, 3/1/2004

Dr. Zhu’s team investigated synaptic plasticity in the Fragile X knockout mouse. They have found that two particular signaling pathways -- small GTPase Ras pathways -- are impaired in the knockout mouse. In these mice, they find very few of the AMPA receptors which are normally at synapses. Lack of AMPA receptors results in reduced synaptic plasticity in the Fragile X mice. This research complemented Dr. Elizabeth Berry-Kravis’s ongoing clinical trial of AMPAkines, compounds specifically designed to enhance the activity of AMPA receptors, so that each existing receptor is more effective. Dr. Zhu and his team are using physiological and molecular biological techniques to investigate the defects in Ras signaling and AMPA receptor trafficking in Fragile X mice. They will test whether Ras-GEF (a protein which activates Ras and is regulated by FMRP) can restore normal delivery of AMPA receptors to synapses. Their findings may point to promising targets for the design of new drugs to treat Fragile X.