Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome.
Fragile X syndrome, caused by the loss of FMR1 gene function and loss of fragile X mental retardation protein (FMRP), is the most commonly inherited form of mental retardation. The syndrome is characterized by associative learning deficits, reduced risk of cancer, dendritic spine dysmorphogenesis, and facial dysmorphism. However, the molecular mechanism that links loss of function of FMR1 to the learning disability remains unclear. Here, we report an examination of small GTPase Ras signaling and synaptic AMPA receptor (AMPA-R) trafficking in cultured slices and intact brains of wild-type and FMR1 knock-out mice. In FMR1 knock-out mice, synaptic delivery of GluR1-, but not GluR2L- and GluR4-containing AMPA-Rs is impaired, resulting in a selective loss of GluR1-dependent long-term synaptic potentiation (LTP). Although Ras activity is upregulated, its downstream MEK (extracellular signal-regulated kinase kinase)-ERK (extracellular signal-regulated kinase) signaling appears normal, and phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB; or Akt) signaling is compromised in FMR1 knock-out mice. Enhancing Ras-PI3K-PKB signaling restores synaptic delivery of GluR1-containing AMPA-Rs and normal LTP in FMR1 knock-out mice. These results suggest aberrant Ras signaling as a novel mechanism for fragile X syndrome and indicate manipulating Ras-PI3K-PKB signaling to be a potentially effective approach for treating patients with fragile X syndrome.
Hu
Hailan
H
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Qin
Yi
Y
Bochorishvili
Genrieta
G
Zhu
Yinghua
Y
van Aelst
Linda
L
Zhu
J Julius
JJ
D000818:Animals; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D009924:Organ Culture Techniques; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
D051860:Fragile X Messenger Ribonucleoprotein 1; D018091:Receptors, AMPA; D018631:ras Proteins; C497684:Fmr1 protein, mouse