Abstract
The postsynaptic density protein PSD-95 influences synaptic AMPA receptor (AMPAR) content and may play a critical role in LTD. Here we demonstrate that the effects of PSD-95 on AMPAR-mediated synaptic responses and LTD can be dissociated. Our findings suggest that N-terminal-domain-mediated dimerization is important for PSD-95's effect on basal synaptic AMPAR function, whereas the C-terminal SH(3)-GK domains are also necessary for localizing PSD-95 to synapses. We identify PSD-95 point mutants (Q15A, E17R) that maintain PSD-95's influence on basal AMPAR synaptic responses yet block LTD. These point mutants increase the proteolysis of PSD-95 within its N-terminal domain, resulting in a C-terminal fragment that functions as a dominant negative likely by scavenging critical signaling proteins required for LTD. Thus, the C-terminal portion of PSD-95 serves a dual function. It is required to localize PSD-95 at synapses and as a scaffold for signaling proteins that are required for LTD.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Cells, Cultured
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Dendritic Spines / physiology
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Disks Large Homolog 4 Protein
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Dose-Response Relationship, Radiation
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Electric Stimulation / methods
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Green Fluorescent Proteins / metabolism
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Hippocampus / cytology
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / physiology*
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Long-Term Synaptic Depression / physiology*
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Models, Biological
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Neurons / physiology*
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Neurons / ultrastructure
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Patch-Clamp Techniques / methods
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Point Mutation / physiology
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Protein Structure, Tertiary / physiology
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Rats
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Rats, Sprague-Dawley
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Receptors, AMPA / physiology
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Synapses / physiology*
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Synaptic Transmission / physiology
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Synaptic Transmission / radiation effects
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Transfection / methods
Substances
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Disks Large Homolog 4 Protein
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Dlg4 protein, rat
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptors, AMPA
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Green Fluorescent Proteins