Open Access Research

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

Hitoshi Nagura12, Yasuyuki Ishikawa3, Katsunori Kobayashi4, Keizo Takao5, Tomo Tanaka1, Kouki Nishikawa6, Hideki Tamura3, Sadao Shiosaka3, Hidenori Suzuki4, Tsuyoshi Miyakawa7, Yoshinori Fujiyoshi2 and Tomoko Doi1*

Author Affiliations

1 Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan

2 Cellular and Structural Physiology Institute, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8601, Japan

3 Laboratory of Functional Neuroscience, Nara Institute of Science and Technology, Ikoma, Nara, 630-0192, Japan

4 Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, Tokyo, 113-8602, Japan

5 Section of Behavior Analysis, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Aichi, 444-8585, Japan

6 Cellular and Structural Physiology Institute, Nagoya University, Furo-cho, chikusa, Nagoya, 464-8601, Japan

7 Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan

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Molecular Brain 2012, 5:43  doi:10.1186/1756-6606-5-43

Published: 26 December 2012

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.

Keywords:
PSD-MAGUK; Synaptic clustering; PDZ domain; PSD-95; Synaptic transmission; Dentate gyrus; Behavioral test battery