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Title: Impaired synaptic clustering of postsynaptic density proteins and altered signal transmission in hippocampal neurons, and disrupted learning behavior in PDZ1 and PDZ2 ligand binding-deficient PSD-95 knockin mice.
Authors: Nagura, Hitoshi
Ishikawa, Yasuyuki
Kobayashi, Katsunori
Takao, Keizo
Tanaka, Tomo
Nishikawa, Kouki
Tamura, Hideki
Shiosaka, Sadao
Suzuki, Hidenori
Miyakawa, Tsuyoshi
Fujiyoshi, Yoshinori
Doi, Tomoko  kyouindb  KAKEN_id
Author's alias: 土井, 知子
Keywords: PSD-MAGUK
Synaptic clustering
PDZ domain
Synaptic transmission
Dentate gyrus
Behavioral test battery
Issue Date: 26-Dec-2012
Publisher: BioMed Central Ltd.
Journal title: Molecular brain
Volume: 5
Thesis number: 43
Abstract: [Background]Postsynaptic density (PSD)-95-like membrane-associated guanylate kinases (PSD-MAGUKs) are scaffold proteins in PSDs that cluster signaling molecules near NMDA receptors. PSD-MAGUKs share a common domain structure, including three PDZ (PDZ1/2/3) domains in their N-terminus. While multiple domains enable the PSD-MAGUKs to bind various ligands, the contribution of each PDZ domain to synaptic organization and function is not fully understood. Here, we focused on the PDZ1/2 domains of PSD-95 that bind NMDA-type receptors, and studied the specific roles of the ligand binding of these domains in the assembly of PSD proteins, synaptic properties of hippocampal neurons, and behavior, using ligand binding-deficient PSD-95 cDNA knockin (KI) mice. [Results]The KI mice showed decreased accumulation of mutant PSD-95, PSD-93 and AMPA receptor subunits in the PSD fraction of the hippocampus. In the hippocampal CA1 region of young KI mice, basal synaptic efficacy was reduced and long-term potentiation (LTP) was enhanced with intact long-term depression. In adult KI mice, there was no significant change in the magnitude of LTP in CA1, but robustly enhanced LTP was induced at the medial perforant path-dentate gyrus synapses, suggesting that PSD-95 has an age- and subregion-dependent role. In a battery of behavioral tests, KI mice showed markedly abnormal anxiety-like behavior, impaired spatial reference and working memory, and impaired remote memory and pattern separation in fear conditioning test. [Conclusions]These findings reveal that PSD-95 including its ligand binding of the PDZ1/2 domains controls the synaptic clustering of PSD-MAGUKs and AMPA receptors, which may have an essential role in regulating hippocampal synaptic transmission, plasticity, and hippocampus-dependent behavior.
Rights: © 2012 Nagura et al.; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI(Published Version): 10.1186/1756-6606-5-43
PubMed ID: 23268962
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