Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity
- University of California, San Francisco, United States
- Max Planck Institute of Experimental Medicine, Germany
- University of Cambridge, United Kingdom
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 axon function and integrity during adulthood and after WM injury.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Multiple Sclerosis Society (FG-1607-25111)
- Lucas Schirmer
European Commission (ERC advanced grant - AxoGLIA)
- Klaus-Armin Nave
National Multiple Sclerosis Society (FG-20102-A-1)
- Andrés Cruz-Herranz
Deutsche Forschungsgemeinschaft (EXC171)
- Wiebke Möbius
- Klaus-Armin Nave
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (P300PB_177927)
- Anne-Katrin Pröbstel
European Commission (ERC advanced grant - MyeliNANO)
- Klaus-Armin Nave
Deutsche Forschungsgemeinschaft (TR43)
- Wiebke Möbius
Deutsche Forschungsgemeinschaft (SCHI 1330/1-1)
- Lucas Schirmer
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (P2SKP3_164938/1)
- Anne-Katrin Pröbstel
Associazione Italiana Sclerosi Multipla (2013/B/4)
- Christian Cordano
Multiple Sclerosis Society (Project grant)
- Robin JM Franklin
Wellcome (Senior investigator grant)
- David H Rowitch
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Collaborative research grant)
- Klaus-Armin Nave
- Robin JM Franklin
- David H Rowitch
National Institutes of Health (NS040511)
- David H Rowitch
California Institute of Regenerative Medicine (Medical Scientist Training Program)
- Kevin W Kelley
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 mouse strains were maintained at the University of California, San Francisco (UCSF) specific pathogen-free animal facility under protocol number AN110094. All animal protocols were approved by and in accordance with the guidelines established by the Institutional Animal Care and Use Committee and Laboratory Animal Resource Center.
Copyright
© 2018, Schirmer et al.
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.
Metrics
-
- 5,002
- views
-
- 1,054
- downloads
-
- 79
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Further reading
-
- Neuroscience
Mental and behavioral disorders are associated with extended period of hot weather as found in heatwaves, but the underlying neural circuit mechanism remains poorly known. The posterior paraventricular thalamus (pPVT) is a hub for emotional processing and receives inputs from the hypothalamic preoptic area (POA), the well-recognized thermoregulation center. The present study was designed to explore whether chronic heat exposure leads to aberrant activities in POA recipient pPVT neurons and subsequent changes in emotional states. By devising an air heating paradigm mimicking the condition of heatwaves and utilizing emotion-related behavioral tests, viral tract tracing, in vivo calcium recordings, optogenetic manipulations, and electrophysiological recordings, we found that chronic heat exposure for 3 weeks led to negative emotional valence and hyperarousal states in mice. The pPVT neurons receive monosynaptic excitatory and inhibitory innervations from the POA. These neurons exhibited a persistent increase in neural activity following chronic heat exposure, which was essential for chronic heat-induced emotional changes. Notably, these neurons were also prone to display stronger neuronal activities associated with anxiety responses to stressful situations. Furthermore, we observed saturated neuroplasticity in the POA-pPVT excitatory pathway after chronic heat exposure that occluded further potentiation. Taken together, long-term aberration in the POA to pPVT pathway offers a neurobiological mechanism of emotional and behavioral changes seen in extended periods of hot weather like heatwaves.
-
- Neuroscience
Intrinsic sensory neurons are an essential part of the enteric nervous system (ENS) and play a crucial role in gastrointestinal tract motility and digestion. Neuronal subtypes in the ENS have been distinguished by their electrophysiological properties, morphology, and expression of characteristic markers, notably neurotransmitters and neuropeptides. Here, we investigated synaptic cell adhesion molecules as novel cell-type markers in the ENS. Our work identifies two type II classic cadherins, Cdh6 and Cdh8, specific to sensory neurons in the mouse colon. We show that Cdh6+ neurons demonstrate all other distinguishing classifications of enteric sensory neurons including marker expression of Calcb and Nmu, Dogiel type II morphology and AH-type electrophysiology and IH current. Optogenetic activation of Cdh6+ sensory neurons in distal colon evokes retrograde colonic motor complexes (CMCs), while pharmacologic blockade of rhythmicity-associated current IH disrupts the spontaneous generation of CMCs. These findings provide the first demonstration of selective activation of a single neurochemical and functional class of enteric neurons and demonstrate a functional and critical role for sensory neurons in the generation of CMCs.
