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A multi-scale model reveals cellular and physiological mechanisms underlying hyperpolarisation-gated synaptic plasticity

View ORCID ProfileYubin Xie, Marcel Kazmierczyk, View ORCID ProfileBruce P. Graham, Mayank B. Dutia, View ORCID ProfileMelanie I. Stefan, Mayank B. Dutia
doi: https://doi.org/10.1101/418228
Yubin Xie
1Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, UK
2Tri-Institutional Training Program in Computational Biology and Medicine, New York, USA
3School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Marcel Kazmierczyk
1Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, UK
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Bruce P. Graham
4Division of Computing Science and Mathematics, University of Stirling, UK
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Mayank B. Dutia
1Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, UK
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Melanie I. Stefan
1Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, UK
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Mayank B. Dutia
1Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, UK
5ZJU-UoE Institute, Zhejiang University School of Medicine, Haining, China
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Abstract

Neurons in the medial vestibular nucleus (MVN) display hyperpolarisation-gated synaptic plasticity, where inhibition believed to come from cerebellar cortical Purkinje cells can induce long-term potentiation (LTP) or long-term depression (LTD) of vestibular nerve afferent synapses. This phenomenon is thought to underlie the plasticity of the vestibulo-ocular reflex (VOR). The molecular and cellular mechanisms involved are largely unknown. Here we present a novel multi-scale computational model, which captures both electrophysiological and biochemical signalling at vestibular nerve synapses on proximal dendrites of the MVN neuron. We show that AMPA receptor phosphorylation at the vestibular synapse depends in complex ways on dendritic calcium influx, which is in turn shaped by patterns of post-synaptic hyperpolarisation and vestibular nerve stimulation. Hyperpolarisation-gated synaptic plasticity critically depends on the activation of LVA calcium channels and on the interplay between CaMKII and PP2B in dendrites of the post-synaptic MVN cell. The extent and direction of synaptic plasticity depend on the strength and duration of hyperpolarisation, and on the relative timing of hyperpolarisation and vestibular nerve stimulation. The multi-scale model thus enables us to explore in detail the interactions between electrophysiological activation and post-synaptic biochemical reaction systems. More generally, this model has the potential to address a wide range of questions about neural signal integration, post-synaptic biochemical reaction systems and plasticity.

Footnotes

  • ↵* melanie.stefan{at}ed.ac.uk

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 23, 2019.
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A multi-scale model reveals cellular and physiological mechanisms underlying hyperpolarisation-gated synaptic plasticity
Yubin Xie, Marcel Kazmierczyk, Bruce P. Graham, Mayank B. Dutia, Melanie I. Stefan, Mayank B. Dutia
bioRxiv 418228; doi: https://doi.org/10.1101/418228
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A multi-scale model reveals cellular and physiological mechanisms underlying hyperpolarisation-gated synaptic plasticity
Yubin Xie, Marcel Kazmierczyk, Bruce P. Graham, Mayank B. Dutia, Melanie I. Stefan, Mayank B. Dutia
bioRxiv 418228; doi: https://doi.org/10.1101/418228

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