Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.

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.

• Authors: Chae-Seok Lim, Elizabeth T Hoang, Kenneth E Viar, Ruth L Stornetta, Michael M Scott, J Julius Zhu
• Journal: Genes & development (Genes Dev) Vol. 28 Issue 3 Pg. 273-89 (Feb 01 2014) ISSN: 1549-5477 [Electronic] United States
• PMID: 24493647 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Agents
• Fmr1 protein, mouse
• Receptors, AMPA
• Serotonin Agents
• Fragile X Mental Retardation Protein
• ras Proteins
• glutamate receptor ionotropic, AMPA 1

Topics

• Animals
• Disease Models, Animal
• Dopamine Agents (pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Fragile X Mental Retardation Protein (genetics, metabolism)
• Fragile X Syndrome (drug therapy)
• Learning (drug effects)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, AMPA (genetics, metabolism)
• Serotonin Agents (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Synapses (drug effects)
• ras Proteins (metabolism)