Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity

Ehrlich, I., Malinow, R. (January 2004) Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J Neurosci, 24 (4). pp. 916-27. ISSN 1529-2401 (Electronic)

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DOI: 10.1523/jneurosci.4733-03.2004


The regulated delivery of AMPA-type glutamate receptors (AMPARs) to synapses is an important mechanism underlying synaptic plasticity. Here, we ask whether the synaptic scaffolding protein PSD-95 (postsynaptic density 95) participates in AMPAR incorporation during two forms of synaptic plasticity. In hippocampal slice cultures, the expression of PSD-95-green fluorescent protein (PSD-95-GFP) increases AMPAR currents by selectively delivering glutamate receptor 1 (GluR1)-containing receptors to synapses, thus mimicking long-term potentiation (LTP). Mutational analysis shows that the N terminal of PSD-95 including the first two PDZ [PSD-95/Discs large (Dlg)/zona occludens-1 (ZO-1)] domains is necessary and sufficient to mediate this effect. Further supporting a role in synaptic plasticity, wild-type PSD-95 occludes LTP and dominant negative forms block LTP. Moreover, we demonstrate that PSD-95 also participates in AMPAR delivery during experience-driven plasticity in vivo. In the barrel cortex from experience-deprived animals, the expression of PSD-95-GFP selectively increases AMPAR currents, mimicking experience-driven plasticity. In nondeprived animals, PSD-95-GFP produces no additional potentiation, indicating common mechanisms between PSD-95-mediated potentiation and experience-driven synaptic strengthening. A dominant negative form of PSD-95 blocks experience-driven potentiation of synapses. Pharmacological analysis in slice cultures reveals that PSD-95 acts downstream of other signaling pathways involved in LTP. We conclude that PSD-95 controls activity-dependent AMPAR incorporation at synapses via PDZ interactions not only during LTP in vitro but also during experience-driven synaptic strengthening by natural stimuli in vivo.

Item Type: Paper
Uncontrolled Keywords: Animals Cell Membrane metabolism Gene Expression Genes Dominant Green Fluorescent Proteins Hippocampus metabolism physiology Intracellular Signaling Peptides and Proteins Long-Term Potentiation physiology Luminescent Proteins genetics Membrane Proteins Mutagenesis Site-Directed Nerve Tissue Proteins genetics/metabolism physiology Neuronal Plasticity physiology Patch-Clamp Techniques Protein Structure Tertiary genetics physiology Protein Transport physiology Rats Receptors AMPA metabolism Recombinant Fusion Proteins genetics metabolism Sensory Deprivation physiology Somatosen/sory Cortex metabolism physiology Synapses metabolism physiology Synaptic Transmission physiology Vibrissae physiology
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > green fluorescent protein
organs, tissues, organelles, cell types and functions > tissues types and functions > hippocampus
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > neural plasticity
CSHL Authors:
Communities: CSHL labs > Malinow lab
Depositing User: CSHL Librarian
Date: 28 January 2004
Date Deposited: 03 Feb 2012 16:11
Last Modified: 06 Nov 2017 21:22
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