RT Journal Article
SR Electronic
T1 Ras Signaling Mechanisms Underlying Impaired GluR1-Dependent Plasticity Associated with Fragile X Syndrome
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7847
OP 7862
DO 10.1523/JNEUROSCI.1496-08.2008
VO 28
IS 31
A1 Hailan Hu
A1 Yi Qin
A1 Genrieta Bochorishvili
A1 Yinghua Zhu
A1 Linda van Aelst
A1 J. Julius Zhu
YR 2008
UL http://www.jneurosci.org/content/28/31/7847.abstract
AB 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.