The Mental Retardation Protein PAK3 Contributes to Synapse Formation and Plasticity in Hippocampus
Open Access
- 1 December 2004
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 24 (48), 10816-10825
- https://doi.org/10.1523/jneurosci.2931-04.2004
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
This publication has 39 references indexed in Scilit:
- Altered Cortical Synaptic Morphology and Impaired Memory Consolidation in Forebrain- Specific Dominant-Negative PAK Transgenic MiceNeuron, 2004
- GIT1 Activates p21-Activated Kinase through a Mechanism Independent of p21 BindingMolecular and Cellular Biology, 2004
- Nonsyndromic X-linked mental retardation: where are the missing mutations?Trends in Genetics, 2003
- Synapse formation is regulated by the signaling adaptor GIT1The Journal of cell biology, 2003
- X‐linked mild non‐syndromic mental retardation with neuropsychiatric problems and the missense mutation A365E in PAK3American Journal of Medical Genetics Part A, 2003
- AMPA Receptor Trafficking and Synaptic PlasticityAnnual Review of Neuroscience, 2002
- Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardationNature Genetics, 2000
- Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spinesNature, 1996
- Identification of a Mouse p21Cdc42/Rac Activated KinasePublished by Elsevier ,1995
- Evidence for silent synapses: Implications for the expression of LTPNeuron, 1995