Abstract
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 Kir4.1 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.
Highlights
Published: 5 February 2022Astrocytes are the most common glial cell type in the central nervous system (CNS).Here, they regulate many physiological functions with importance for the correct functionality of the surrounding neurons
The hallmark characteristics of Spinal muscular atrophy (SMA) are the reduction of survival of motor neuron (SMN) protein with subsequent loss of spinal motor neurons
We performed immunostaining of spinal cord slices against SMN protein and SMI-32 as a marker for spinal motor neurons to investigate these characteristics
Summary
Published: 5 February 2022Astrocytes are the most common glial cell type in the central nervous system (CNS).Here, they regulate many physiological functions with importance for the correct functionality of the surrounding neurons. It is not surprising that misfunction of astrocytes contributes to many neurological disorders such as epilepsy, brain ischemia, Alzheimer’s disease (AD), Huntington’s disease (HD), or amyotrophic lateral sclerosis (ALS) [5,6,7,8,9] For those disorders, dysfunctions in both the inward rectifier potassium channel Kir4.1 responsible for the uptake of extracellular potassium or the excitatory amino acid transporter 1 or 2 (EAAT1 or 2) contributing to the uptake of synaptically released glutamate, directly result in neuron hyperexcitability and potential apoptotic processes [10,11,12,13,14,15]
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