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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axons / pathology
  • Humans
  • Leukoencephalopathies / genetics*
  • Leukoencephalopathies / physiopathology
  • Mice
  • Mice, Knockout
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Potassium Channels, Inwardly Rectifying / genetics*
  • Seizures / genetics*
  • Seizures / physiopathology
  • Spinal Cord / metabolism
  • Spinal Cord / physiopathology

Substances

  • Kcnj10 (channel)
  • Potassium Channels, Inwardly Rectifying