Tag-Trigger-Consolidation: A Model of Early and Late Long-Term-Potentiation and Depression

Claudia Clopath,Lorric Ziegler,Lars Büsing,Eleni Vasilaki,Wulfram Gerstner,Lyle J Graham

doi:10.1371/journal.pcbi.1000248

Claudia Clopath, Lorric Ziegler + Show 4 more

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https://doi.org/10.1371/journal.pcbi.1000248

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Abstract

Changes in synaptic efficacies need to be long-lasting in order to serve as a substrate for memory. Experimentally, synaptic plasticity exhibits phases covering the induction of long-term potentiation and depression (LTP/LTD) during the early phase of synaptic plasticity, the setting of synaptic tags, a trigger process for protein synthesis, and a slow transition leading to synaptic consolidation during the late phase of synaptic plasticity. We present a mathematical model that describes these different phases of synaptic plasticity. The model explains a large body of experimental data on synaptic tagging and capture, cross-tagging, and the late phases of LTP and LTD. Moreover, the model accounts for the dependence of LTP and LTD induction on voltage and presynaptic stimulation frequency. The stabilization of potentiated synapses during the transition from early to late LTP occurs by protein synthesis dynamics that are shared by groups of synapses. The functional consequence of this shared process is that previously stabilized patterns of strong or weak synapses onto the same postsynaptic neuron are well protected against later changes induced by LTP/LTD protocols at individual synapses.

Highlights

Changes in the connection strength between neurons in response to appropriate stimulation are thought to be the physiological basis for learning and memory formation [1,2]
Despite the complexity of the molecular processes, synaptic plasticity has experimentally been characterized by a small set of distinct phenomena such as shortterm plasticity [44] as well as early and late phases of Long-Term Potentiation (LTP) and Long-Term Depression (LTD) [13]
While calmodulin dependent kinase II (CaMKII) is necessary for induction of long-term potentiation [46], it is probably too narrow to focus modeling studies only on a single or a few kinases such as CaMKII and neglect other proteins and signaling cascades that are involved in synaptic maintenance [13]

Summary

Introduction

Changes in the connection strength between neurons in response to appropriate stimulation are thought to be the physiological basis for learning and memory formation [1,2]. LTP can be induced at groups of synapses by strong ‘tetanic’ high-frequency stimulation of the presynaptic pathway [3] while stimulation at lower frequency leads to LTD Dudek. LTP can be induced at groups of synapses by strong ‘tetanic’ high-frequency stimulation of the presynaptic pathway [3] while stimulation at lower frequency leads to LTD Dudek92 Both LTP and LTD can be induced at a single synapse or a small number of synaptic contacts if presynaptic activity is paired with either a depolarization of the postsynaptic membrane [5,7] or tightly timed postsynaptic spikes [8,9]. A candidate molecule, involved in the tag signaling LTP induction in apical dendrites of hippocampal neurons, is the calcium-calmodulin dependent kinase II (CaMKII) [13]. A candidate protein involved in the maintenance of potentiated hippocampal synapses is the protein kinase Mf (PKMf) [11,14]

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