Long-Term Potentiation Induced by θ Frequency Stimulation Is Regulated by a Protein Phosphatase-1-Operated Gate
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Long-term potentiation (LTP) can be induced in the Schaffer collateral→CA1 synapse of hippocampus by stimulation in the θ frequency range (5–12 Hz), an effect that depends on activation of the cAMP pathway. We investigated the mechanisms of the cAMP contribution to this form of LTP in the rat hippocampal slice preparation. θ pulse stimulation (TPS; 150 stimuli at 10 Hz) by itself did not induce LTP, but the addition of either the β-adrenergic agonist isoproterenol or the cAMP analog 8-bromo-cAMP (8-Br-cAMP) enabled TPS-induced LTP. The isoproterenol effect was blocked by postsynaptic inhibition of cAMP-dependent protein kinase. Several lines of evidence indicated that cAMP enabled LTP by blocking postsynaptic protein phosphatase-1 (PP1). Activators of the cAMP pathway reduced PP1 activity in the CA1 region and increased the active form of inhibitor-1, an endogenous inhibitor of PP1. Postsynaptic injection of activated inhibitor-1 mimicked the LTP-enabling effect of cAMP pathway stimulation. TPS evoked complex spiking when isoproterenol was present. However, complex spiking was not sufficient to enable TPS-induced LTP, which additionally required the inhibition of postsynaptic PP1. PP1 inhibition seems to promote the activation of Ca 2+/calmodulin-dependent protein kinase (CaMKII), because (1) a CaMKII inhibitor blocked the induction of LTP by TPS paired with either isoproterenol or activated inhibitor-1 and (2) CaMKII in area CA1 was activated by the combination of TPS and 8-Br-cAMP but not by either stimulus alone. These results indicate that the cAMP pathway enables TPS-induced LTP by inhibiting PP1, thereby enhancing Ca 2+-independent CaMKII activity.
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PP1 inhibition facilitates the induction of LTP by promoting activation of CaMKII.
“In support of such a balance, it has been reported that PP1 inhibition facilitates the induction of LTP, by promoting activation of CaMKII (392).”
From Synaptic memory and CaMKII (2023) · cites this paper as [392]
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- Authors
- Brown, G. P., Blitzer, R. D., Connor, J. H., Wong, T., Shenolikar, S., Iyengar, R., & Landau, E. M.
- Affiliations
- United States Department of Veterans Affairs (US)
- Duke University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2000-11-01
- Volume
- 20
- Issue
- 21
- Pages
- 7880-7887
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6772713
- OpenAlex
- W1485679631
- Cited by
- 98
- References
- 44
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 1 · 2018: 4 · 2017: 5 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 2
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns033646-03)
- National Institute of General Medical Sciences (GM5408, F32GM018887)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK5204)
- National Institute of Neurological Disorders and Stroke (NS33646)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- long-term potentiation, protein phosphatase 1, cAMP pathway, protein kinase A, inhibitor-1, CaMKII, Schaffer collateral-CA1 synapses, hippocampus, isoproterenol, 8-bromo-cAMP, synaptic plasticity
- MeSH terms
- Action Potentials, Cyclic AMP, Adrenergic beta-Agonists, Animals, Electric Stimulation, Hippocampus, Male, Synaptic Transmission, Neuronal Plasticity, Phosphoprotein Phosphatases, Proteins, Theta Rhythm, 8-Bromo Cyclic Adenosine Monophosphate, Signal Transduction, Ion Channel Gating, Rats, Sprague-Dawley, Long-Term Potentiation, Calcium-Calmodulin-Dependent Protein Kinases, Receptors, AMPA, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Rats, Protein Phosphatase 1, Calcium-Calmodulin-Dependent Protein Kinase Type 2, In Vitro Techniques
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