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NJIT Mathematical Biology Seminar

Note special day and location:
November 17 (Thursday), 2005, 4:00 pm

Cullimore Lecture Hall 3
(Cullimore Hall, 1st floor)

New Jersey Institute of Technology

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Transitions in a bistable model of the calcium/calmodulin-dependent protein kinase phosphatase system in response to STDP protocols

Michael Graupner

CNRS, Laboratory of Neurophysics and Physiology
Université Paris 5 René Descartes

The calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the induction of long-term post-synaptic modifications following calcium entry. Experiments suggest that long-term synaptic changes are all-or none swich-like events. The biochemical network involving CaMKII and its regulating protein signaling cascade has been hypothesized to be a bistable realization of such a switch. However, it is still unclear whether LTP/LTD protocols lead to transitions between the two states in realistic models of such a network.

A detailed biochemical model of the CaMKII autophosphorylation and the protein signaling cascade governing the CaMKII dephosphorylation is presented. Dephosphorylation is mediated by protein phosphatase 1 whose activity is indirectly regulated by the Ca(2+)-dependent balance between protein kinase A and calcineurin. All of these proteins are known to be involved in synaptic plasticity.

As reported by Zhabotinsky (Biophys J, 2000), two stable states of the system exist at resting intracellular Ca(2+) concentration: a weakly-(DOWN) and a highly-phosphorylated (UP) state of the CaMKII. A transition from the DOWN to the UP state can be achieved by high calcium elevations, with an UP-shifting threshold which is determined by the competing CaMKII autophosphorylation and dephosphorylation dynamics. Intermediate Ca(2+) concentrations enhance CaMKII dephosphorylation due to a relative increase in calcineurin activity. This results in depotentiation - switching from the UP to the DOWN state - during respective Ca(2+) transients. The transitions in both directions, from the DOWN to the UP state and vice versa, are achieved in response to Ca(2+) levels which resemble those which are present during LTP and LTD induction protocols. Finally, it is shown that the CaMKII system can qualitatively reproduce results of plasticity outcomes in response to the spike-timing dependent synaptic plasticity (STDP) paradigm