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Induction and binary expression of LTP/LTD in a minimal model of the CaMKII system

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The calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the induction of long-term post-synaptic modifications following synaptic activation. Experiments suggest that these long-term synaptic changes are all-or none switch-like events between discrete states [1]. The biochemical network involving CaMKII and its regulating protein signaling cascade has been hypothesized to durably maintain the evoked synaptic state in the form of a bistable switch [2, 3]. However, it is still unclear whether different experimental LTP/LTD protocols lead to corresponding transitions between the two states in models of such a network. Furthermore, the biochemical mechanisms and signaling cascades giving rise to the non-linearities exhibited during LTP/LTD induction remain elusive.

Starting from a detailed biochemical model, a minimal model describing the CaMKII phosphorylation (activation) level is presented which preserves the features of a comprehensive description. CaMKII autophosphorylation is governed by calcium/calmodulin binding and is a highly cooperative process. CaMKII dephosphorylation is mediated by protein phosphatase 1 whose activity is indirectly regulated by a calcium-dependent balance of kinase (protein kinase A) and phosphatase (calcineurin) activity. These two competing effects are implemented via phosphorylation- and dephosphorylation rates changing the CaMKII phosphorylation level and are realized as simple step functions activating above different calcium levels.

The model retains previous results [2, 3], two stable states of CaMKII phosphorylation exist at resting intracellular calcium concentrations. With an appropriate positioning of the de-/phosphorylation thresholds, high calcium transients can switch the system from the weakly-(DOWN) to the highly-phosphorylated (UP) state of the CaMKII (similar to a LTP event) and intermediate Ca(2+) concentrations can lead to switching from the UP to the DOWN state (similar to a LTD event). As a basic principle, this can be achieved if the CaMKII dephosphorylation activates at lower Ca(2+) levels than phosphorylation. This simple approach allows us to address whether or not a read-out system using the calcium level as the sole input signal can account for the non-linearities exhibited during LTP/LTD induction. It is shown that this simple realization of the CaMKII system can qualitatively reproduce experimental plasticity results in response to spike-timing dependent plasticity (STDP) protocols (spike-pairs and -triplets), pre-synaptic stimulation protocols and pairing protocols. Our investigations show that a minimal model of the CaMKII protein network can account for both induction (through LTP/LTD-like transitions) and storage (due to its bistability) of synaptic changes. However, we suggest that the dynamics of the global calcium time course play a crucial role for the sign of synaptic changes alongside the crosstalk between signaling cascades that include the one considered here.

References

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    O'Connor DH, Wittenberg GM, Wang SS-H: Graded bidirectional synaptic plasticity is composed of switch-like unitary events. Proc Natl Acad Sci USA. 2005, 102: 9679-84. 10.1073/pnas.0502332102.

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    Zhabotinsky AM: Bistability in the Ca(2+)/calmodulin-dependent protein kinase-phosphatase system. Biophys J. 2000, 79: 2211-2221.

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    Okamoto H, Ichikawa K: Switching characteristics of a model for biochemical-reaction networks describing autophosphorylation versus dephosphorylation of Ca(2+)/calmodulin-dependent protein kinase II. Biol Cybern. 2000, 82: 35-47. 10.1007/PL00007960.

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Correspondence to Michael Graupner.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Graupner, M., Brunel, N. Induction and binary expression of LTP/LTD in a minimal model of the CaMKII system. BMC Neurosci 8, P94 (2007) doi:10.1186/1471-2202-8-S2-P94

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Keywords

  • Minimal Model
  • Synaptic Change
  • Bistable Switch
  • Experimental Plasticity
  • Pairing Protocol