Altered potassium channel distribution and composition in myelinated axons suppresses hyperexcitability following injury

  1. Margarita Calvo  Is a corresponding author
  2. Natalie Richards
  3. Annina B Schmid
  4. Alejandro Barroso
  5. Lan Zhu
  6. Dinka Ivulic
  7. Ning Zhu
  8. Philipp Anwandter
  9. Manzoor A Bhat
  10. Felipe A Court
  11. Stephen B McMahon
  12. David LH Bennett
  1. Wolfson CARD, United Kingdom
  2. King's College London, United Kingdom
  3. Oxford University, United Kingdom
  4. Kings College London, United Kingdom
  5. Facultad de Ciencias Biologicas- Pontificia Universidad Catolica de Chile, Chile
  6. Facultad de Medicina, - Pontificia Universidad Catolica de Chile, Chile
  7. UT Health Science Center at San Antonio, United States
  8. Pontificia Universidad Catolica de Chile, Chile
  9. university of oxford, United Kingdom

Abstract

Neuropathic pain following peripheral nerve injury is associated with hyperexcitability in damaged myelinated sensory axons, which begins to normalise over time. We investigated the composition and distribution of shaker-type-potassium channels (Kv1 channels) within the nodal complex of myelinated axons following injury. At the neuroma that forms after damage, expression of Kv1.1 and 1.2 (normally localised to the juxtaparanode) was markedly decreased. In contrast Kv1.4 and 1.6, which were hardly detectable in the naïve state, showed increased expression within juxtaparanodes and paranodes following injury, both in rats and humans. Within the dorsal root (a site remote from injury) we noted a redistribution of Kv1-channels towards the paranode. Blockade of Kv1 channels with αDTX after injury reinstated hyperexcitability of A-fibre axons and enhanced mechanosensitivity. Changes in the molecular composition and distribution of axonal Kv1 channels, therefore represents a protective mechanism to suppress the hyperexcitability of myelinated sensory axons that follows nerve injury.

Article and author information

Author details

  1. Margarita Calvo

    Kings College London, Wolfson CARD, London, United Kingdom
    For correspondence
    mcalvob@uc.cl
    Competing interests
    The authors declare that no competing interests exist.
  2. Natalie Richards

    Wolfson CARD, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Annina B Schmid

    Nuffield department of clinical neurosciences, Oxford University, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Alejandro Barroso

    Wolfson CARD, Kings College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Lan Zhu

    Wolfson CARD, Kings College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Dinka Ivulic

    Departamento de Fisiologia, Facultad de Ciencias Biologicas- Pontificia Universidad Catolica de Chile, Santiago, Chile
    Competing interests
    The authors declare that no competing interests exist.
  7. Ning Zhu

    Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Philipp Anwandter

    Departamento Ortopedia y Traumatologia, Facultad de Medicina, - Pontificia Universidad Catolica de Chile, Santiago, Chile
    Competing interests
    The authors declare that no competing interests exist.
  9. Manzoor A Bhat

    Department of Physiology, School of Medicine, UT Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Felipe A Court

    Millenium Nucleus for Regenerative Biology, Faculty of Biology, Pontificia Universidad Catolica de Chile, Santiago, Chile
    Competing interests
    The authors declare that no competing interests exist.
  11. Stephen B McMahon

    Wolfson CARD, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. David LH Bennett

    Nuffield department of clinical neuroscience, university of oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with UK Home Office and Pontificia Universidad Catolica's regulations.Experimental protocols were reviewed and approved by "Coordinación de Ética, Bioética y Seguridad de las investigaciones UC" (experiments done in Chile- Protocol CBB230/2013) and were performed in accordance to the UK Home Office regulations (experiments done in the UK). We report this study in compliance with the ARRIVE guidelines (20 points checklist).

Human subjects: Informed consent, and consent to publish, was obtained from all subjects to collect and analyze nerve samples before surgery. Subjects underwent surgery by indication of their physician and samples were obtained from biological tissue that was otherwise due to be incinerated.The study protocol was assessed and approved by the Ethics Scientific Committee of the School of Medicine Pontificia Universidad Catolica de Chile (reference number 14-389)

Copyright

© 2016, Calvo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,678
    views
  • 752
    downloads
  • 45
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Margarita Calvo
  2. Natalie Richards
  3. Annina B Schmid
  4. Alejandro Barroso
  5. Lan Zhu
  6. Dinka Ivulic
  7. Ning Zhu
  8. Philipp Anwandter
  9. Manzoor A Bhat
  10. Felipe A Court
  11. Stephen B McMahon
  12. David LH Bennett
(2016)
Altered potassium channel distribution and composition in myelinated axons suppresses hyperexcitability following injury
eLife 5:e12661.
https://doi.org/10.7554/eLife.12661

Share this article

https://doi.org/10.7554/eLife.12661

Further reading

    1. Neuroscience
    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.

    1. Neuroscience
    Gáspár Oláh, Rajmund Lákovics ... Gábor Tamás
    Research Article

    Human-specific cognitive abilities depend on information processing in the cerebral cortex, where the neurons are significantly larger and their processes longer and sparser compared to rodents. We found that, in synaptically connected layer 2/3 pyramidal cells (L2/3 PCs), the delay in signal propagation from soma to soma is similar in humans and rodents. To compensate for the longer processes of neurons, membrane potential changes in human axons and/or dendrites must propagate faster. Axonal and dendritic recordings show that the propagation speed of action potentials (APs) is similar in human and rat axons, but the forward propagation of excitatory postsynaptic potentials (EPSPs) and the backward propagation of APs are 26 and 47% faster in human dendrites, respectively. Experimentally-based detailed biophysical models have shown that the key factor responsible for the accelerated EPSP propagation in human cortical dendrites is the large conductance load imposed at the soma by the large basal dendritic tree. Additionally, larger dendritic diameters and differences in cable and ion channel properties in humans contribute to enhanced signal propagation. Our integrative experimental and modeling study provides new insights into the scaling rules that help maintain information processing speed albeit the large and sparse neurons in the human cortex.