Email updates

Keep up to date with the latest news and content from Molecular Brain and BioMed Central.

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

For all author emails, please log on.

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