Serotonergic Rescue of Synaptic Plasticity in FMR1 Knockout Mice

With $306,000 in grants from FRAXA Research Foundation, Dr. Julius Zhu at the University of Virginia examined the effects of several drugs (some already in common use in Fragile X, such as Buspar and Abilify) which manipulate specific serotonin receptors and their impacts on synaptic plasticity (LTP and LTD).

Results published: Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model
$306,000 Grants
Julius Zhu, PhD
Principal Investigator

Chae-Seok Lim, PhD
FRAXA Postdoctoral Fellow

University of Virginia
2010-2012, 2008-9, 2003-4, 2001 FRAXA Research Grants
$306,000 over 8 Years

We had 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 explained 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), new effective treatments for Fragile X still seems years away. As an alternative approach, we planned 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 was 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.

Explore Current Fragile X Research

FRAXA-funded researchers around the world are leading the way towards effective treatments and ultimately a cure.

Share via
Copy link