Journal
NEURON
Volume 98, Issue 2, Pages 306-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2018.03.010
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Funding
- Multiple Sclerosis Society of Great Britain and Northern Ireland [207495]
- Medical Scientist Training Program [T32GM007618]
- California Institute of Regenerative Medicine pre-doctoral fellowship [TG201153]
- German Research Foundation (DFG) [SCHI 1330/1-1]
- Pew Scholars Award
- NIMH [K08MH104417]
- Paul Allen Foundation Distinguished Investigator Program
- ALS Association
- NEI [EY002162]
- NINDS [NS040511]
- Howard Hughes Medical Institute
- Cambridge NIHR Biomedical Research Center
- Wellcome Trust
- MRC [MR/P008658/1] Funding Source: UKRI
- Medical Research Council [MC_PC_12009, MR/P008658/1] Funding Source: researchfish
- Wellcome Trust [101149/Z/13/Z] Funding Source: researchfish
- Wellcome Trust [101149/Z/13/Z] Funding Source: Wellcome Trust
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Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast alpha-motor neurons (F alpha MNs) 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 F alpha MN 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 F alpha MN 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.
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