Journal
CELLS
Volume 11, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/cells11030558
Keywords
spinal muscular atrophy; SMA; survival of motor neuron; SMN; siRNA; astrocytes; spinal cord; glia-neuron interaction; neuromuscular disorders
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This study investigates the role of spinal astrocytes in the pathogenesis of late-onset SMA forms. Using a mouse model and SMA-like astrocytes, they observed the activation of spinal astrocytes, reduction of certain proteins, and impaired glutamate uptake and potassium uptake. These findings demonstrate the crucial role of spinal astrocytes in the development of late-onset SMA.
Spinal muscular atrophy (SMA) is a motor neuron disorder leading to progressive loss of ventral horn neurons resulting in muscle wasting. Here we investigate the contribution of spinal astrocytes to the pathogenesis of late-onset SMA forms using a mouse model. Furthermore, we generated SMA-like astrocytes using survival of motor neuron (SMN) siRNA transfection techniques. In the SMA mouse model, the activation of spinal astrocytes and the reduction of the inward rectifier potassium channel K-ir4.1 and excitatory amino acid transporter 1 (EAAT1) were observed at postnatal day (P) 28, preceding the loss of spinal motor neurons appearing earliest at P42. Using SMA-like astrocytes, we could mimic the modulation of spinal astrocytes of the mouse model in a dish and perform electrophysiological assessments and functional assays. In SMA-like astrocytes, glutamate uptake was diminished due to a reduction in EAAT1. Furthermore, patch-clamp measurements revealed reduced potassium uptake into astrocytes with membrane depolarization. Additionally, exposure of healthy spinal motor neurons to a conditioned medium of SMA-like astrocytes resulted in increased firing frequency. These data demonstrate spinal astrocytes' crucial role in the late-onset SMA forms' pathogenesis.
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