Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model
- Chae-Seok Lim1,
- Elizabeth T. Hoang1,2,
- Kenneth E. Viar1,
- Ruth L. Stornetta1,
- Michael M. Scott1 and
- J. Julius Zhu1,3,4
- 1Department of Pharmacology,
- 2Department of Psychology,
- 3Department of Neuroscience, University of Virginia School of Medicine, University of Virginia College of Arts and Sciences, Charlottesville, Virginia 22908, USA
Abstract
Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT2B-Rs) or dopamine (DA) subtype 1-like receptors (D1-Rs) and/or those inhibiting 5HT2A-Rs or D2-Rs moderately enhance Ras–PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras–PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.
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Footnotes
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↵4 Corresponding author
E-mail jjzhu{at}virginia.edu
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.232470.113.
- Received October 8, 2013.
- Accepted December 27, 2013.
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