An Essential Role for Protein Phosphatases in Hippocampal Long-Term Depression
Abstract
The effectiveness of long-term potentiation (LTP) as a mechanism for information storage would be severely limited if processes that decrease synaptic strength did not also exist. In area CA1 of the rat hippocampus, prolonged periods of low-frequency afferent stimulation elicit a long-term depression (LTD) that is specific to the stimulated input. The induction of LTD was blocked by the extracellular application of okadaic acid or calyculin A, two inhibitors of protein phosphatases 1 and 2A. The loading of CA1 cells with microcystin LR, a membrane-impermeable protein phosphatase inhibitor, or calmodulin antagonists also blocked or attenuated LTD. The application of calyculin A after the induction of LTD reversed the synaptic depression, suggesting that phosphatase activity is required for the maintenance of LTD. These findings indicate that the synaptic activation of protein phosphatases plays an important role in the regulation of synaptic transmission.
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LTD is induced by the activation of a high-affinity Ca2+ cascade resulting in the activation of PP1.
“In a series of classic studies it was found that LTD is induced by the activation of a high-affinity Ca2+ cascade resulting in the activation of PP1 (395–397).”
From Synaptic memory and CaMKII (2023) · cites this paper as [395]
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“…Yang et al., 2010), while protein phosphatases PP1, PP2A, and calcineurin (CaN) (also known as PP2B) dephosphorylate GluA1 S845 and remove receptors by endocytosis during LTD (Mulkey et al., 1993; Kameyama et al., 1998; Lee et al., 1998, 2000, 2003, 2010; Beattie et al., 2000; Ashby et al., 2004).”
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“In support of such a balance, it has been reported that PP1 inhibition facilitates the induction of LTP, by promoting activation of CaMKII (392).”
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- Authors
- Mulkey, R. M., Herron, C. E., & Malenka, R. C.
- Affiliations
- University of California, San Francisco (US)
- ORCID
- Malenka, Robert C.
- Venue
- Science
- Published
- 1993-08-20
- Volume
- 261
- Issue
- 5124
- Pages
- 1051-1055
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1972384396
- Cited by
- 699
- References
- 0
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 11 · 2023: 7 · 2022: 9 · 2021: 14 · 2020: 12 · 2019: 7 · 2018: 10 · 2017: 9 · 2016: 16 · 2015: 11 · 2014: 18 · 2013: 26 · 2012: 25
- FWCI
- 19.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5f32mh010306-02, 5r29mh045334-05)
- National Institute of Mental Health (MH10306, MH45334, MH00942)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- long-term depression, protein phosphatase, protein phosphatase 1, protein phosphatase 2A, hippocampal CA1, okadaic acid, calyculin A, microcystin-LR, calmodulin antagonists, synaptic plasticity, synaptic transmission, long-term potentiation, low-frequency stimulation
- MeSH terms
- Animals, Calcium, Calmodulin, Electric Stimulation, Ethers, Cyclic, Hippocampus, Marine Toxins, Synaptic Transmission, Oxazoles, Peptides, Cyclic, Phosphoprotein Phosphatases, Phosphorylation, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Okadaic Acid, Rats, Microcystins
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