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.
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.
