Excitatory neurons are more disinhibited than inhibitory neurons by chloride dysregulation in the spinal dorsal horn

  1. Kwan Yeop Lee
  2. Stéphanie Ratté
  3. Steven A Prescott  Is a corresponding author
  1. The Hospital for Sick Children, Canada

Abstract

Neuropathic pain is a debilitating condition caused by the abnormal processing of somatosensory input. Synaptic inhibition in the spinal dorsal horn plays a key role in that processing. Mechanical allodynia – the misperception of light touch as painful – occurs when inhibition is compromised. Disinhibition is due primarily to chloride dysregulation caused by hypofunction of the potassium-chloride co-transporter KCC2. Here we show, in rats, that excitatory neurons are disproportionately affected. This is not because chloride is differentially dysregulated in excitatory and inhibitory neurons, but, rather, because excitatory neurons rely more heavily on inhibition to counterbalance strong excitation. Receptive fields in both cell types have a center-surround organization but disinhibition unmasks more excitatory input to excitatory neurons. Differences in intrinsic excitability also affect how chloride dysregulation affects spiking. These results deepen understanding of how excitation and inhibition are normally balanced in the spinal dorsal horn, and how their imbalance disrupts somatosensory processing.

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Article and author information

Author details

  1. Kwan Yeop Lee

    Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Stéphanie Ratté

    Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Steven A Prescott

    Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada
    For correspondence
    steve.prescott@sickkids.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3827-4512

Funding

Canadian Institutes of Health Research (PJT-153161)

  • Steven A Prescott

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Claire Wyart, Hôpital Pitié-Salpêtrière, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, France

Ethics

Animal experimentation: All experimental procedures were approved by the Animal Care Committee at the Hospital for Sick Children (Animal Use Protocol #22919 and #22576) and were performed in accordance to guidelines from the Canadian Council on Animal Care. For in vivo experiments, animals were anesthetized with urethane (20% in normal saline; 1.2 g/kg i.p.). To prepare slices for in vitro experiments, animals were anesthetized with 4% isoflurane.

Version history

  1. Received: June 27, 2019
  2. Accepted: November 18, 2019
  3. Accepted Manuscript published: November 19, 2019 (version 1)
  4. Version of Record published: December 2, 2019 (version 2)

Copyright

© 2019, Lee 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.

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  1. Kwan Yeop Lee
  2. Stéphanie Ratté
  3. Steven A Prescott
(2019)
Excitatory neurons are more disinhibited than inhibitory neurons by chloride dysregulation in the spinal dorsal horn
eLife 8:e49753.
https://doi.org/10.7554/eLife.49753

Share this article

https://doi.org/10.7554/eLife.49753

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