Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength
Authors
Kelley, Kevin W
Ben Haim, Lucile
Schirmer, Lucas
Tyzack, Giulia
Tolman, Michaela
Miller, John
Tsai, Hui-Hsin
Chang, Sandra M
Molofsky, Anna V
Yang, Yongjie
Patani, Rickie
Ullian, Erik M
Journal Title
Neuron
Publisher
Elsevier
Type
Article
This Version
VoR
Metadata
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Kelley, K. W., Ben Haim, L., Schirmer, L., Tyzack, G., Tolman, M., Miller, J., Tsai, H., et al. Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength. Neuron https://doi.org/10.1016/j.neuron.2018.03.010
Abstract
Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast a-motor neurons (FaMNs) 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 FaMN 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 FaMN 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.
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
MRC (MR/P008658/1)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1016/j.neuron.2018.03.010
This record's URL: https://www.repository.cam.ac.uk/handle/1810/275014
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