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Loss of SLC9A6/NHE6 impairs nociception in a mouse model of Christianson syndrome

Petitjean, Hugues, Fatima, Tarheen, Mouchbahani-Constance, Stephanie, Davidova, Albena, Ferland, Catherine E., Orlowski, John, Sharif-Naeini, Reza·2020·Pain
DOI 10.1097/j.pain.0000000000001961PMC PMC7566297
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Abstract

Children diagnosed with Christianson syndrome (CS), a rare X-linked neurodevelopmental disorder characterized by intellectual disability, epilepsy, ataxia, and mutism, also suffer from hyposensitivity to pain. This places them at risk of sustaining serious injuries that often go unattended. Christianson syndrome is caused by mutations in the alkali cation/proton exchanger SLC9A6/NHE6 that regulates recycling endosomal pH homeostasis and trafficking. Yet, it remains unclear how defects in this transporter lead to altered somatosensory functions. In this study, we validated a Nhe6 knockout (KO) mouse as a model of CS and used it to identify the cellular mechanisms underlying the elevated pain tolerance observed in CS patients. Within the central nervous system, NHE6 immunolabelling is detected in a small percentage of cortical neurons involved in pain processing, including those within the primary somatosensory and the anterior cingulate cortices as well as the periaqueductal gray. Interestingly, it is expressed in a larger percentage of nociceptors. Behaviourally, Nhe6 KO mice have decreased nocifensive responses to acute noxious thermal, mechanical, and chemical (ie, capsaicin) stimuli. The reduced capsaicin sensitivity in the KO mice correlates with a decreased expression of the transient receptor potential channel TRPV1 at the plasma membrane and capsaicin-induced Ca 2+ influx in primary cultures of nociceptors. These data indicate that NHE6 is a significant determinant of nociceptor function and pain behaviours, vital sensory processes that are impaired in CS.

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  • Other neurobehavioral phenotypes described for Slc9a6- mice recapitulate symptoms in Christianson syndrome patients, for example, hyposensitivity to pain.

    “Other neurobehavioral phenotypes have been described for Slc9a6- mice, which also recapitulate symptoms in Christianson syndrome patients, for example, hyposensitivity to pain (Petitjean et al., 2020).”

    From NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load (2021) · cites this paper as Petitjean et al., 2020

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Metadata

Authors
Petitjean, H., Fatima, T., Mouchbahani-Constance, S., Davidova, A., Ferland, C. E., Orlowski, J., & Sharif-Naeini, R.
Affiliations
  • Department of Physiology, Cell Information Systems Group, McGill University, Montreal, QC, Canada
  • Department of Anesthesia, Shriners Hospital for Children-Canada, McGill University, Montreal, QC, Canada
Venue
Pain
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2020-06-15
Volume
161
Issue
11
Pages
2619-2628
ISSN
  • 0304-3959
  • 1872-6623
DOI
10.1097/j.pain.0000000000001961
PMC
PMC7566297
Cited by
19
References
3
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (unspecified)

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