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

作者：Lim Chae Seok; Hoang Elizabeth T; Viar Kenneth E; Stornetta Ruth L; Scott Michael M; Zhu J Julius^*

来源：Genes & Development, 2014, 28(3): 273-289.

DOI：10.1101/gad.232470.113

• autism
• AMPA receptor trafficking
• Ras-PI3K signaling
• mental retardation
• cocktail drug treatment

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 (5HT(2B)-Rs) or dopamine (DA) subtype 1-like receptors (D-1-Rs) and/or those inhibiting 5HT(2A)-Rs or D-2-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.

• 出版日期2014-2-1