Temporal Sensitivity of Protein Kinase A Activation in Late-Phase Long Term Potentiation
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Protein kinases play critical roles in learning and memory and in long term potentiation (LTP), a form of synaptic plasticity. The induction of late-phase LTP (L-LTP) in the CA1 region of the hippocampus requires several kinases, including CaMKII and PKA, which are activated by calcium-dependent signaling processes and other intracellular signaling pathways. The requirement for PKA is limited to L-LTP induced using spaced stimuli, but not massed stimuli. To investigate this temporal sensitivity of PKA, a computational biochemical model of L-LTP induction in CA1 pyramidal neurons was developed. The model describes the interactions of calcium and cAMP signaling pathways and is based on published biochemical measurements of two key synaptic signaling molecules, PKA and CaMKII. The model is stimulated using four 100 Hz tetani separated by 3 sec (massed) or 300 sec (spaced), identical to experimental L-LTP induction protocols. Simulations show that spaced stimulation activates more PKA than massed stimulation, and makes a key experimental prediction, that L-LTP is PKA-dependent for intervals larger than 60 sec. Experimental measurements of L-LTP demonstrate that intervals of 80 sec, but not 40 sec, produce PKA-dependent L-LTP, thereby confirming the model prediction. Examination of CaMKII reveals that its temporal sensitivity is opposite that of PKA, suggesting that PKA is required after spaced stimulation to compensate for a decrease in CaMKII. In addition to explaining the temporal sensitivity of PKA, these simulations suggest that the use of several kinases for memory storage allows each to respond optimally to different temporal patterns.
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Models have described the dynamics of biochemical reactions that transduce stimuli into LTP.
“In recent years, models have described the dynamics of the biochemical reactions that transduce stimuli into LTP86–88.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [87]
The induction of PKA-sensitive LTP requires multiple episodes of stimuli with proper interepisode intervals.
“The induction of PKA-sensitive LTP requires multiple episodes of stimuli with proper interepisode intervals (Woo et al., 2003;Kim et al., 2010;Park et al., 2014;Park et al., 2016).”
From The Brain-Enriched MicroRNA miR-9-3p Regulates Synaptic Plasticity and Memory (2016) · cites this paper as Kim et al., 2010
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- Authors
- Kim, M., Huang, T., Abel, T., & Blackwell, K. T.
- Affiliations
- George Mason University (US)
- University of Pennsylvania (US)
- Corresponding author
- Blackwell, Kim T.
- Venue
- PLoS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-02-26
- Volume
- 6
- Issue
- 2
- Pages
- e1000691
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC2829045
- OpenAlex
- W2071938721
- Cited by
- 72
- References
- 87
- Citations by year
- 2025: 5 · 2024: 5 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2018: 6 · 2017: 3 · 2016: 8 · 2015: 5 · 2014: 11 · 2013: 10 · 2012: 3
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Science Foundation (R01 AA18060)
- National Institutes of Health (5r01aa018060-05, NIH-R01)
- National Institute on Alcohol Abuse and Alcoholism (R01 AA-18060, R01-AA018060)
- 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
- protein kinase A, CaMKII, calcium signaling, cAMP signaling, temporal sensitivity, CA1 pyramidal neurons, hippocampus, synaptic plasticity, memory storage, learning and memory
- MeSH terms
- Cyclic AMP, Animals, Calcium, Computer Simulation, Dopamine, Enzyme Activation, Models, Neurological, Time Factors, Signal Transduction, Long-Term Potentiation, Cyclic AMP-Dependent Protein Kinases, Computational Biology, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2, CA1 Region, Hippocampal
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