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Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately
Open accessAbstract
Persistent dendritic spine enlargement is associated with stable long-term potentiation (LTP), and the latter is thought to underlie long-lasting memories. Extracellular proteolytic remodeling of the synaptic microenvironment could be important for such plasticity, but whether or how proteolytic remodeling contributes to persistent modifications in synapse structure and function is unknown. Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is activated perisynaptically after LTP induction and required for LTP maintenance. Here, by monitoring spine size and excitatory postsynaptic potentials (EPSPs) simultaneously with combined 2-photon time-lapse imaging and whole-cell recordings from hippocampal neurons, we find that MMP-9 is both necessary and sufficient to drive spine enlargement and synaptic potentiation concomitantly. Both structural and functional MMP-driven forms of plasticity are mediated through β1-containing integrin receptors, are associated with integrin-dependent cofilin inactivation within spines, and require actin polymerization. In contrast, postsynaptic exocytosis and protein synthesis are both required for MMP-9-induced potentiation, but not for initial MMP-9-induced spine expansion. However, spine expansion becomes unstable when postsynaptic exocytosis or protein synthesis is blocked, indicating that the 2 forms of plasticity are expressed independently but require interactions between them for persistence. When MMP activity is eliminated during theta-stimulation-induced LTP, both spine enlargement and synaptic potentiation are transient. Thus, MMP-mediated extracellular remodeling during LTP has an instructive role in establishing persistent modifications in both synapse structure and function of the kind critical for learning and memory.
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“MMP-9 activity has been primarily associated with the growth and strengthening of synapses (Wang et al., 2008; Szepesi et al., 2014).”
From Light reintroduction after dark exposure reactivates plasticity in adults via perisynaptic activation of MMP-9 (2017) · cites this paper as Wang et al., 2008
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Metadata
- Authors
- Wang, X.-B., Bozdagi, O., Nikitczuk, J. S., Zhai, Z. W., Zhou, Q., & Huntley, G. W.
- Affiliations
- Departments of aNeurology and
- Icahn School of Medicine at Mount Sinai (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-12-09
- Volume
- 105
- Issue
- 49
- Pages
- 19520-19525
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2614793
- OpenAlex
- W1977637789
- Cited by
- 316
- References
- 48
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 10 · 2023: 10 · 2022: 14 · 2021: 13 · 2020: 22 · 2019: 17 · 2018: 23 · 2017: 15 · 2016: 20 · 2015: 21 · 2014: 26 · 2013: 23 · 2012: 32
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- Whitehall Foundation
- National Institute of Mental Health (R01MH075783, MH-075783)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- MMP-9, long-term potentiation, synaptic plasticity, extracellular proteolysis, beta1 integrin, cofilin, actin polymerization, protein synthesis, hippocampal neurons, memory formation
- MeSH terms
- Actins, Animals, Exocytosis, Extracellular Matrix, Neuronal Plasticity, Phosphorylation, Integrins, Rats, Sprague-Dawley, Long-Term Potentiation, Excitatory Postsynaptic Potentials, Matrix Metalloproteinase 9, Dendritic Spines, Actin Depolymerizing Factors, Rats
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