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Serotonergic rescue of synaptic plasticity in FMR1 knockout mice
 
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Julius Zhu, Ph.D.
Principal Investigator
Chae-Seok Lim, Ph.D.
Postdoctoral Fellow
University of Virgina

FRAXA Awards:
   $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).

Updated by Julius Zhu, 4/2010

We have recently demonstrated that

1) aberrant Ras-PI3K-PKB/AKT signaling is responsible for the impaired synaptic delivery of GluR1 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 GluR1 knockout mice. Serotonin receptors (5HT-Rs) regulate postsynaptic plasticity and, in addition, a few serotonergic compounds are among the best medications used in treating fragile X. Moreover, our preliminary data show that activation of certain 5HT-Rs stimulates synaptic delivery of GluR1 in FMR1 knockout mice, suggesting a novel specific pharmacological target for treating fragile X.

Based on these findings, we propose to test the hypothesis that 5HT-R antagonists and/or 5HT uptake inhibitors in combination with agonists of other receptors, may effectively restore normal LTP in FMR1 knockout mice. The findings should provide the scientific foundation to guide future development of drugs to treat fragile X.

2003-4: FMRP Regulates Small GTPase Ras Signaling and Glutamate Receptor Trafficking
By Katie Clapp, 3/2004


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.



 
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Editor/writers: Katie Clapp, MS, and Michael Tranfaglia, MD. Updated 5/23/10. All rights reserved. Disclaimer Created by Dave Fullam and Icovia