A model of the roles of essential kinases in the induction and expression of late long-term potentiation

Authors

Paul Smolen, Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, USA.
Douglas A. Baxter, Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, USA.
John H. Byrne, Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, USA.

Publication Date

4-15-2006

Journal

Biophys J. 2006 Apr 15;90(8):2760-75. Epub 2006 Jan 13.Click here to read

Abstract

The induction of late long-term potentiation (L-LTP) involves complex interactions among second-messenger cascades. To gain insights into these interactions, a mathematical model was developed for L-LTP induction in the CA1 region of the hippocampus. The differential equation-based model represents actions of protein kinase A (PKA), MAP kinase (MAPK), and CaM kinase II (CAMKII) in the vicinity of the synapse, and activation of transcription by CaM kinase IV (CAMKIV) and MAPK. L-LTP is represented by increases in a synaptic weight. Simulations suggest that steep, supralinear stimulus-response relationships between stimuli (e.g., elevations in [Ca(2+)]) and kinase activation are essential for translating brief stimuli into long-lasting gene activation and synaptic weight increases. Convergence of multiple kinase activities to induce L-LTP helps to generate a threshold whereby the amount of L-LTP varies steeply with the number of brief (tetanic) electrical stimuli. The model simulates tetanic, -burst, pairing-induced, and chemical L-LTP, as well as L-LTP due to synaptic tagging. The model also simulates inhibition of L-LTP by inhibition of MAPK, CAMKII, PKA, or CAMKIV. The model predicts results of experiments to delineate mechanisms underlying L-LTP induction and expression. For example, the cAMP antagonist RpcAMPs, which inhibits L-LTP induction, is predicted to inhibit ERK activation. The model also appears useful to clarify similarities and differences between hippocampal L-LTP and long-term synaptic strengthening in other systems.

Keywords

Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinase Type 4, Calcium-Calmodulin-Dependent Protein Kinases, Computer Simulation, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Enzyme Activation, Hippocampus, Humans, Long-Term Potentiation, Mitogen-Activated Protein Kinases, Models, Neurological, Protein-Serine-Threonine Kinases, Synapses, Transcriptional Activation

Comments

PMCID: PMC1414565

doi: 10.1529/biophysj.105.072470