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Coactivation and timing-dependent integration of synaptic potentiation and depression

Abstract

Neuronal synaptic connections can be potentiated or depressed by paired pre- and postsynaptic spikes, depending on the spike timing. We show that in cultured rat hippocampal neurons a calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated potentiation process and a calcineurin-mediated depression process can be activated concomitantly by spike triplets or quadruplets. The integration of the two processes critically depends on their activation timing. Depression can cancel previously activated potentiation, whereas potentiation tends to override previously activated depression. The time window for potentiation to dominate is about 70 ms, beyond which the two processes cancel. These results indicate that the signaling machinery underlying spike timing–dependent plasticity (STDP) may be separated into functional modules that are sensitive to the spatiotemporal dynamics (rather than the amount) of calcium influx. The timing dependence of modular interaction provides a quantitative framework for understanding the temporal integration of STDP.

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Figure 1: Triplet experiments showing asymmetric temporal integration of STDP.
Figure 2: Effects of CaMKII inhibition on the induction and temporal integration of STDP.
Figure 3: Effects of calcineurin inhibition on the induction and temporal integration of STDP.
Figure 4: STDP integration after biased triplets with unequal positive and negative timings suggests dominant role of potentiation.
Figure 6: Normalization of STDP integration.
Figure 5: Asymmetric integration follows quadruplet stimuli.
Figure 7: Asymmetric time window of STDP integration.

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Acknowledgements

We thank P. Lau for providing data for some STDP experiments; E. Aizenman, K. Kandler, P. Lau and J. Rubin for comments on the manuscript and members of the Bi lab for discussions. This work was supported by grants from Burroughs Wellcome Fund (Career Award in the Biomedical Sciences) and the National Institute of Mental Health (R01 MH066962) to G.Q.B.

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Correspondence to Guo-Qiang Bi.

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Wang, HX., Gerkin, R., Nauen, D. et al. Coactivation and timing-dependent integration of synaptic potentiation and depression. Nat Neurosci 8, 187–193 (2005). https://doi.org/10.1038/nn1387

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