Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome

Hu, H. L., Qin, Y., Bochorishvili, G., Zhu, Y. H., Van Aelst, L., Zhu, J. J. (July 2008) Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome. Journal of Neuroscience, 28 (31). pp. 7847-7862. ISSN 0270-6474

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URL: http://www.ncbi.nlm.nih.gov/pubmed/18667617
DOI: 10.1523/JNEUROSCI.1496-08.2008

Abstract

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.

Item Type: Paper
Uncontrolled Keywords: autism AMPA receptor trafficking Ras-PI3K signaling cancer risk mental retardation dendritic spine dysmorphogenesis facial dysmorphism MENTAL-RETARDATION PROTEIN AMPA-RECEPTOR TRAFFICKING FMR1 KNOCKOUT MICE LONG-TERM POTENTIATION NEOCORTICAL PYRAMIDAL NEURONS BETA-GAMMA-SUBUNITS SYNAPTIC PLASTICITY MOUSE MODEL DENDRITIC SPINES PHOSPHOINOSITIDE 3-KINASE
Subjects: diseases & disorders > congenital hereditary genetic diseases
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
diseases & disorders > congenital hereditary genetic diseases > fragile X syndrome
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > glutamate receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Van Aelst lab
Depositing User: Matt Covey
Date: July 2008
Date Deposited: 25 Feb 2013 20:42
Last Modified: 25 Feb 2013 20:42
PMCID: PMC2553221
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27602

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