Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD.
Open accessAbstract
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.
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Acute knockdown of PSD-95 in brain slices impairs LTD.
“In addition, acute knockdown of PSD-95 in brain slices impairs LTD [25],[26].”
From Regulated RalBP1 Binding to RalA and PSD-95 Controls AMPA Receptor Endocytosis and LTD (2009) · cites this paper as [26]
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- Authors
- Xu, W., Schlüter, O. M., Steiner, P., Czervionke, B. L., Sabatini, B., & Malenka, R. C.
- Affiliations
- Stanford Medicine (US)
- Max Planck Society (DE)
- Harvard University (US)
- Corresponding author
- Malenka, Robert C.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 57
- Issue
- 2
- Pages
- 248-262
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3147180
- OpenAlex
- W2146326162
- Cited by
- 193
- References
- 5
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 13 · 2020: 8 · 2019: 10 · 2018: 12 · 2017: 8 · 2016: 9 · 2015: 5 · 2014: 7 · 2013: 22 · 2012: 10
- FWCI
- 8.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2024 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Funders
- McKnight Foundation
- National Institutes of Health
- National Institute of Mental Health (MH 063394, MH075220, R37MH063394, F32MH075220, R01MH063394, R01MH118298, R00MH080310, K99MH080310, MH080310)
- National Institute of Neurological Disorders and Stroke (R01NS052707)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- PSD-95, synaptic plasticity, long-term depression, AMPA receptors, postsynaptic density, SH3 domain, proteolysis, synaptic protein localization
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Animals, Newborn, Cells, Cultured, Dose-Response Relationship, Radiation, Electric Stimulation, Hippocampus, Humans, Membrane Proteins, Models, Biological, Synaptic Transmission, Neurons, Synapses, Transfection, Rats, Sprague-Dawley, Point Mutation, Protein Structure, Tertiary, Receptors, AMPA, Patch-Clamp Techniques, Long-Term Synaptic Depression, Intracellular Signaling Peptides and Proteins, Dendritic Spines, Green Fluorescent Proteins, Rats
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