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The Journal of Neuroscience, July 30, 2008, 28(31):7847-7862; doi:10.1523/JNEUROSCI.1496-08.2008

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Cellular/Molecular
Ras Signaling Mechanisms Underlying Impaired GluR1-Dependent Plasticity Associated with Fragile X Syndrome

Hailan Hu,^1 * Yi Qin,^1,3 * Genrieta Bochorishvili,¹ Yinghua Zhu,¹ Linda van Aelst,³ and J. Julius Zhu^1,2

Departments of ¹Pharmacology and ²Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia 22908, and ³Center for Cancer Research, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724

Correspondence should be addressed to J. Julius Zhu, Department of Pharmacology, University of Virginia School of Medicine, 1300 Jefferson Park Avenue, Charlottesville, VA 22908. Email: jjzhu{at}virginia.edu

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.

Key words: autism; AMPA receptor trafficking; Ras–PI3K signaling; cancer risk; mental retardation; dendritic spine dysmorphogenesis; facial dysmorphism

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Received Dec. 26, 2007; revised May 21, 2008; accepted June 23, 2008.

Correspondence should be addressed to J. Julius Zhu, Department of Pharmacology, University of Virginia School of Medicine, 1300 Jefferson Park Avenue, Charlottesville, VA 22908. Email: jjzhu{at}virginia.edu

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