Abstract
SummaryDiversified 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.
Highlights
Astrocytes (AS) carry out general functions in the central nervous system (CNS), including blood-brain barrier formation, regulation of synaptogenesis, and the maintenance of metabolic, ionic, and neurotransmitter homeostasis (Allen, 2014; Allen and Barres, 2009; Matyash and Kettenmann, 2010)
Is there a role for local ventral horn AS to selectively maintain the physiological properties and function of motor neuron (MN) subtypes, and is this role disrupted in amyotrophic lateral sclerosis (ALS)? We have previously shown that ventral horn AS-encoded function of Sema3a is essential for the survival of aMNs (Molofsky et al, 2014)
Consistent with Kir4.1 expression dictated in part by neuron-derived factors, we found that spinal cord Kir4.1 (Kcnj10) levels were downregulated in a genetic MN ablation model at embryonic day 18.5 (E18.5) (Figure S3)
Summary
Astrocytes (AS) carry out general functions in the central nervous system (CNS), including blood-brain barrier formation, regulation of synaptogenesis, and the maintenance of metabolic, ionic, and neurotransmitter homeostasis (Allen, 2014; Allen and Barres, 2009; Matyash and Kettenmann, 2010). Because AS are pervasive throughout the CNS and their processes tile within domains, they are key environmental determinants for neural circuits. We have proposed that regionally diversified AS could become ‘‘optimized’’ to enhance local function (Freeman and Rowitch, 2013; Molofsky et al, 2012). Coordination of voluntary movement is complex and requires diversified motor neuron (MN) subtypes that form region- and muscle-specific interactions (Kanning et al, 2010). The relationship between local AS specialization, neuron subtype selective support, and neural circuit function remains poorly understood
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