Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength.
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.
|Year of Publication
2018 04 18
|PubMed Central ID
R01 NS040511 / NS / NINDS NIH HHS / United States
T32 GM007618 / GM / NIGMS NIH HHS / United States
MR/P008658/1 / MRC_ / Medical Research Council / United Kingdom
R01 MH106490 / MH / NIMH NIH HHS / United States
K08 MH104417 / MH / NIMH NIH HHS / United States
WT_ / Wellcome Trust / United Kingdom
MC_PC_12009 / MRC_ / Medical Research Council / United Kingdom
P30 EY002162 / EY / NEI NIH HHS / United States