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タイトル: | 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. |
著者: | Nagura, Hitoshi Ishikawa, Yasuyuki Kobayashi, Katsunori Takao, Keizo Tanaka, Tomo Nishikawa, Kouki Tamura, Hideki Shiosaka, Sadao Suzuki, Hidenori Miyakawa, Tsuyoshi Fujiyoshi, Yoshinori Doi, Tomoko |
著者名の別形: | 土井, 知子 |
キーワード: | PSD-MAGUK Synaptic clustering PDZ domain PSD-95 Synaptic transmission Dentate gyrus Behavioral test battery |
発行日: | 26-Dec-2012 |
出版者: | BioMed Central Ltd. |
誌名: | Molecular brain |
巻: | 5 |
論文番号: | 43 |
抄録: | [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. |
著作権等: | © 2012 Nagura et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
URI: | http://hdl.handle.net/2433/178671 |
DOI(出版社版): | 10.1186/1756-6606-5-43 |
PubMed ID: | 23268962 |
出現コレクション: | 学術雑誌掲載論文等 |
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