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Elife. 2018 Sep 11;7. pii: e36428. doi: 10.7554/eLife.36428.

Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity.

Author information

1
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States.
2
Department of Pediatrics, University of California, San Francisco, San Francisco, United States.
3
Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.
4
Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
5
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
6
Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
7
Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
8
Department of Neurology, University of California, San Francisco, San Francisco, United States.
9
Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States.
10
Department of Ophthalmology, University of California, San Francisco, San Francisco, United States.
11
Department of Neurosurgery, University of California, San Francisco, San Francisco, United States.

Abstract

Glial support is critical for normal axon function and can become dysregulated in white matter (WM) disease. In humans, loss-of-function mutations of KCNJ10, which encodes the inward-rectifying potassium channel KIR4.1, causes seizures and progressive neurological decline. We investigated Kir4.1 functions in oligodendrocytes (OLs) during development, adulthood and after WM injury. We observed that Kir4.1 channels localized to perinodal areas and the inner myelin tongue, suggesting roles in juxta-axonal K+ removal. Conditional knockout (cKO) of OL-Kcnj10 resulted in late onset mitochondrial damage and axonal degeneration. This was accompanied by neuronal loss and neuro-axonal dysfunction in adult OL-Kcnj10 cKO mice as shown by delayed visual evoked potentials, inner retinal thinning and progressive motor deficits. Axon pathologies in OL-Kcnj10 cKO were exacerbated after WM injury in the spinal cord. Our findings point towards a critical role of OL-Kir4.1 for long-term maintenance of axonal function and integrity during adulthood and after WM injury.

KEYWORDS:

Kir4.1 (KCNJ10); mouse; neurobiology; neurodegeneration; neuroscience; oligodendrocytes; visual System; white matter

PMID:
30204081
PMCID:
PMC6167053
DOI:
10.7554/eLife.36428
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

LS filed a patent for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis (WO2015166057A1), WM, CZ, AC, LB, CC, LS, KK, BS, GT, AP, JW, JS, MD, DM, SC, KS, AG, RF, DR No competing interests declared, KN Reviewing editor, eLife

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