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 miceReportar como inadecuado




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 - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Molecular Brain

, 5:43

First Online: 26 December 2012Received: 09 October 2012Accepted: 22 December 2012

Abstract

BackgroundPostsynaptic 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.

ResultsThe 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.

ConclusionsThese 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.

KeywordsPSD-MAGUK Synaptic clustering PDZ domain PSD-95 Synaptic transmission Dentate gyrus Behavioral test battery AbbreviationsPSDPostsynaptic density

MAGUKsMembrane-associated guanylate kinases

PSD-MAGUKPSD-95 like membrane-associated guanylate kinase

SH3Src homology-3

GKGuanylate kinase

KIKnockin

KOKnockout

LTPLong-term potentiation

LTDLong-term depression

TARPsTransmembrane AMPAR regulatory proteins

fEPSPsfield excitatory postsynaptic potentials

ASCFArtificial cerebrospinal fluid

PPRPaired-pulse ratio.

Electronic supplementary materialThe online version of this article doi:10.1186-1756-6606-5-43 contains supplementary material, which is available to authorized users.

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Autor: Hitoshi Nagura - Yasuyuki Ishikawa - Katsunori Kobayashi - Keizo Takao - Tomo Tanaka - Kouki Nishikawa - Hideki Tamura - Sa

Fuente: https://link.springer.com/



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