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.
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.
authors.affiliation: Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nagura
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Keizo
authors.initials: K
authors.lastname: Takao
authors.forename: Tomo
authors.initials: T
authors.lastname: Tanaka
authors.forename: Kouki
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Tamura
authors.forename: Sadao
authors.initials: S
authors.lastname: Shiosaka
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujiyoshi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Doi
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001007:Anxiety / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal; D000076122:Disks Large Homolog 4 Protein; D005239:Fear / Q000502:physiology; D055879:Gene Knock-In Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051528:Guanylate Kinases / Q000737:chemistry / Q000378:metabolism*; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D007858:Learning; D008024:Ligands; D017774:Long-Term Potentiation / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D013569:Synapses / Q000473:pathology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C485184:enhanced green fluorescent protein; C033652:postsynaptic density proteins; D049452:Green Fluorescent Proteins; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases