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A Model of the Roles of Essential Kinases in the Induction and Expression of Late Long-Term Potentiation

Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas

Correspondence: Address reprint requests to John H. Byrne, Dept. of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas-Houston Medical School, PO Box 20708, Houston, TX 77225. Tel.: 713-500-5602; Fax: 713-500-0623; E-mail: john.h.byrne{at}uth.tmc.edu.

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 [Ca²⁺]) 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.

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				P. Smolen, D. A. Baxter, and J. H. Byrne Bistable MAP kinase activity: a plausible mechanism contributing to maintenance of late long-term potentiation Am J Physiol Cell Physiol, February 1, 2008; 294(2): C503 - C515. [Abstract] [Full Text] [PDF]