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

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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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Kwan Yeop Lee

Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
Stéphanie Ratté

Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
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.

"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.

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.

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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.