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Neuron. 2018 Apr 18;98(2):306-319.e7. doi: 10.1016/j.neuron.2018.03.010. Epub 2018 Apr 5.

Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength.

Author information

1
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Pediatrics and Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK; The Francis Crick Institute, London NW1 1AT, UK.
3
Sackler School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
4
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
5
John van Geest Centre for Brain Repair and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB20QQ, UK.
6
Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Pediatrics and Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Paediatrics and Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB20QQ, UK. Electronic address: dhr25@medschl.cam.ac.uk.

Abstract

Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast α-motor neurons (FαMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report that ventral horn astrocytes express the inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) around MNs in a VGLUT1-dependent manner. Loss of astrocyte-encoded Kir4.1 selectively altered FαMN size and function and led to reduced peak strength. Overexpression of Kir4.1 in astrocytes was sufficient to increase MN size through activation of the PI3K/mTOR/pS6 pathway. Kir4.1 was downregulated cell autonomously in astrocytes derived from amyotrophic lateral sclerosis (ALS) patients with SOD1 mutation. However, astrocyte Kir4.1 was dispensable for FαMN survival even in the mutant SOD1 background. These findings show that astrocyte Kir4.1 is essential for maintenance of peak strength and suggest that Kir4.1 downregulation might uncouple symptoms of muscle weakness from MN cell death in diseases like ALS.

KEYWORDS:

Kir4.1; amyotrophic lateral sclerosis; astrocyte diversity; fast-twitch muscle; motor neuron; neurodegeneration; peak strength; spinal cord development

PMID:
29606582
PMCID:
PMC5919779
DOI:
10.1016/j.neuron.2018.03.010
[Indexed for MEDLINE]
Free PMC Article

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