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The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus

Nikonenko, Irina
Nodé-Langlois, Roxanne
Moosmayer, Marlyse
Parisi-Jourdain, Lorena
Published in The Journal of neuroscience. 2004, vol. 24, no. 48, p. 10816-10825
Abstract Mutations of the gene coding for PAK3 (p21-activated kinase 3) are associated with X-linked, nonsyndromic forms of mental retardation (MRX) in which the only distinctive clinical feature is the cognitive deficit. The mechanisms through which PAK3 mutation produces the mental handicap remain unclear, although an involvement in the mechanisms that regulate the formation or plasticity of synaptic networks has been proposed. Here we show, using a transient transfection approach, that antisense and small interfering RNA-mediated suppression of PAK3 or expression of a dominant-negative PAK3 carrying the human MRX30 mutation in rat hippocampal organotypic slice cultures results in the formation of abnormally elongated dendritic spines and filopodia-like protrusions and a decrease in mature spine synapses. Ultrastructural analysis of the changes induced by expression of PAK3 carrying the MRX30 mutation reveals that many elongated spines fail to express postsynaptic densities or contact presynaptic terminals. These defects are associated with a reduced spontaneous activity, altered expression of AMPA-type glutamate receptors, and defective long-term potentiation. Together, these data identify PAK3 as a key regulator of synapse formation and plasticity in the hippocampus and support interpretations that these defects might contribute to the cognitive deficits underlying this form of mental retardation.
Keywords Amino Acid SubstitutionAnimalsBiolisticsCell Line, Tumor/ultrastructureCodon, NonsenseCognition Disorders/genetics/physiopathologyDendrites/ultrastructureGenes, DominantHippocampus/drug effects/metabolism/ultrastructureHumansLong-Term PotentiationMental Retardation, X-Linked/ genetics/physiopathology/psychologyMiceMorphogenesisMutation, MissenseNIH 3T3 CellsNeuroblastoma/pathologyOrgan Culture TechniquesProtein Structure, TertiaryProtein-Serine-Threonine Kinases/chemistry/deficiency/genetics/ physiologyPseudopodia/ultrastructurePyramidal Cells/physiologyRNA, Antisense/pharmacology/toxicityRNA, Small Interfering/pharmacology/toxicityRatsReceptors, AMPA/deficiencyRecombinant Fusion Proteins/physiologyTransfectionP21-Activated Kinases
PMID: 15574732
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Other version: http://www.jneurosci.org/cgi/reprint/24/48/10816.pdf
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BODA, Bernadett et al. The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. In: The Journal of neuroscience, 2004, vol. 24, n° 48, p. 10816-10825. doi: 10.1523/JNEUROSCI.2931-04.2004 https://archive-ouverte.unige.ch/unige:10198

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Deposited on : 2010-08-06

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