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

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.

• Authors: Bernadett Boda, Stefano Alberi, Irina Nikonenko, Roxanne Node-Langlois, Pascal Jourdain, Marlyse Moosmayer, Lorena Parisi-Jourdain, Dominique Muller
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 24 Issue 48 Pg. 10816-25 (Dec 01 2004) ISSN: 1529-2401 [Electronic] United States
• PMID: 15574732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Codon, Nonsense
• RNA, Antisense
• RNA, Small Interfering
• Receptors, AMPA
• Recombinant Fusion Proteins
• PAK3 protein, human
• Pak3 protein, mouse
• Pak3 protein, rat
• Protein Serine-Threonine Kinases
• p21-Activated Kinases

Topics

• Amino Acid Substitution
• Animals
• Biolistics
• Cell Line, Tumor (ultrastructure)
• Codon, Nonsense
• Cognition Disorders (genetics, physiopathology)
• Dendrites (ultrastructure)
• Genes, Dominant
• Hippocampus (drug effects, metabolism, ultrastructure)
• Humans
• Long-Term Potentiation
• Mental Retardation, X-Linked (genetics, physiopathology, psychology)
• Mice
• Morphogenesis
• Mutation, Missense
• NIH 3T3 Cells
• Neuroblastoma (pathology)
• Organ Culture Techniques
• Protein Serine-Threonine Kinases (chemistry, deficiency, genetics, physiology)
• Protein Structure, Tertiary
• Pseudopodia (ultrastructure)
• Pyramidal Cells (physiology)
• RNA, Antisense (pharmacology, toxicity)
• RNA, Small Interfering (pharmacology, toxicity)
• Rats
• Receptors, AMPA (deficiency)
• Recombinant Fusion Proteins (physiology)
• Transfection
• p21-Activated Kinases