Temporal sensitivity of protein kinase a activation in late-phase long term potentiation

MyungSook Kim; Ted Huang; Ted Abel; Kim T Blackwell

doi:10.1371/journal.pcbi.1000691

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Temporal sensitivity of protein kinase a activation in late-phase long term potentiation

Journal article

Open access

Temporal sensitivity of protein kinase a activation in late-phase long term potentiation

MyungSook Kim, Ted Huang, Ted Abel and Kim T Blackwell

PLoS computational biology, Vol.6(2), pp.e1000691-e1000691

02/26/2010

DOI: 10.1371/journal.pcbi.1000691

PMCID: PMC2829045

PMID: 20195498

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Abstract

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.

Computational Biology - methods

Signal Transduction

Calcium - metabolism

Cyclic AMP-Dependent Protein Kinases - physiology

Animals

Time Factors

Computer Simulation

Long-Term Potentiation - physiology

CA1 Region, Hippocampal - metabolism

Mice

Enzyme Activation

Models, Neurological

Cyclic AMP - metabolism

Dopamine - metabolism

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism

Details

Title: Subtitle: Temporal sensitivity of protein kinase a activation in late-phase long term potentiation
Creators: MyungSook Kim - George Mason University, The Krasnow Institute for Advanced Studies, Fairfax, Virginia, United States of America
Ted Huang
Ted Abel
Kim T Blackwell
Resource Type: Journal article
Publication Details: PLoS computational biology, Vol.6(2), pp.e1000691-e1000691
DOI: 10.1371/journal.pcbi.1000691
PMID: 20195498
PMCID: PMC2829045
NLM abbreviation: PLoS Comput Biol
ISSN: 1553-734X
eISSN: 1553-7358
Publisher: United States
Grant note: R01 AA18060 / NIAAA NIH HHS R01 AA018060 / NIAAA NIH HHS
Language: English
Date published: 02/26/2010
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9984065827902771

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