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

Lucas Schirmer,Andrés Cruz-Herranz,Jung Hyung Sin,Boguslawa Sadowski,Garrett Timmons,Jackie N Wright,Anne-Katrin Pröbstel,Chao Zhao,Christian Cordano,Daniel E Morrison,Michael Devereux,Lucile Ben Haim,Khalida Sabeur,Wiebke Möbius,Lawrence R Shiow ,Klaus‐Armin Nave ,Ari J Green ,Kevin W Kelley ,Robin J.m Franklin ,Sam K C Chang ,David H Rowitch

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.

Highlights

Glial support of axons is essential for the maintenance of normal function in the central nervous system (CNS) [1,2]
As Kir4.1 channels are assembled as homo- and heterotetramers 81 with Kir5.1, we investigated the expression of both proteins throughout development [9,30]
Levels of Kcnj10 transcripts were higher in myelinating OLs compared to OL progenitor cells (OPCs) in vitro, whereas Kcnj16 mRNA decreased during OL maturation (Figure 1 – figure supplement 1B–C) [33,34]

Summary

Introduction

Glial support of axons is essential for the maintenance of normal function in the central nervous system (CNS) [1,2]. Exchange and buffering of ions such as K+ between astrocytes (AS) and neurons have been well described and led to the current understanding that those cells are major regulators of neuron excitability [6,7,8]. Not much is known about OL-dependent regulation of axonal excitability through buffering of ions like K+ during action potential propagation. We focused on Kir4.1 (Kcnj10), a highly conserved ATP- and pH-sensitive K+ channel expressed in both AS and OL cells of the CNS [9,10,11].

Methods

Results

Conclusion