Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.
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.
Department of Pharmacology.
Chae-Seok
CS
Lim
Elizabeth T
ET
Hoang
Kenneth E
KE
Viar
Ruth L
RL
Stornetta
Michael M
MM
Scott
J Julius
JJ
Zhu
D000818:Animals; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000188:drug therapy*; D007858:Learning / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects*; D018631:ras Proteins / Q000378:metabolism*
D015259:Dopamine Agents; D051860:Fragile X Messenger Ribonucleoprotein 1; D018091:Receptors, AMPA; D018490:Serotonin Agents; D018631:ras Proteins; C497684:Fmr1 protein, mouse
AMPA receptor trafficking; Ras–PI3K signaling; autism; cocktail drug treatment; mental retardation