The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors

Nadif Kasri, N., Nakano-Kobayashi, A., Malinow, R., Li, B., Van Aelst, L. (June 2009) The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors. Genes Dev, 23 (11). pp. 1289-1302. ISSN 0890-9369

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URL: http://www.ncbi.nlm.nih.gov/pubmed/19487570
DOI: 10.1101/gad.1783809

Abstract

Oligophrenin-1 (OPHN1) encodes a Rho-GTPase-activating protein (Rho-GAP) whose loss of function has been associated with X-linked mental retardation (MR). The pathophysiological role of OPHN1, however, remains poorly understood. Here we show that OPHN1 through its Rho-GAP activity plays a critical role in the activity-dependent maturation and plasticity of excitatory synapses by controlling their structural and functional stability. Synaptic activity through NMDA receptor activation drives OPHN1 into dendritic spines, where it forms a complex with AMPA receptors, and selectively enhances AMPA-receptor-mediated synaptic transmission and spine size by stabilizing synaptic AMPA receptors. Consequently, decreased or defective OPHN1 signaling prevents glutamatergic synapse maturation and causes loss of synaptic structure, function, and plasticity. These results imply that normal activity-driven glutamatergic synapse development is impaired by perturbation of OPHN1 function. Thus, our findings link genetic deficits in OPHN1 to glutamatergic dysfunction and suggest that defects in early circuitry development are an important contributory factor to this form of MR.

Item Type: Paper
Uncontrolled Keywords: Rho GTPase-activating protein Oligophrenin-1 glutamatergic function AMPA receptor actin cytoskeleton mental retardation LONG-TERM POTENTIATION DENDRITIC SPINE MORPHOLOGY CEREBELLAR HYPOPLASIA TYROSINE PHOSPHORYLATION VENTRICULAR ENLARGEMENT SPATIAL MEMORY SMALL GTPASES IN-VIVO GENE HIPPOCAMPUS
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > AMPA receptor
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 > mental retardation
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions
organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions > synapse
CSHL Authors:
Communities: CSHL labs > Li lab
CSHL labs > Malinow lab
CSHL labs > Van Aelst lab
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Microscopy Service
Depositing User: Matt Covey
Date: June 2009
Date Deposited: 20 Feb 2013 14:26
Last Modified: 03 Nov 2017 20:10
PMCID: PMC2701582
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27444

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