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bioRxiv · 10.1101/2024.10.11.617793

Functional contribution of astrocytic Kir4.1 channels to spasticity after spinal cord injury

Barbay, T.·Pecchi, E.·Ramirez Franco, J. J.·Ivanov, A.·Brocard, F.·Rouach, N.·BOS, R.
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Abstract

Spasticity, a prevalent motor issue characterized by network hyperexcitability, causes pain and discomfort, with existing treatments offering limited relief. While past research has focused on neuronal factors, the role of astrocytes in spasticity has been overlooked. This study explores the potential of restoring astrocytic potassium (K+) uptake to reduce spasticity following SCI. Astrocytes buffer extracellular K+ via Kir4.1 channels, preventing neuronal hyperexcitability. Following spinal cord injury (SCI), Kir4.1 levels decrease at the injury site, though the consequences and mechanisms of this reduction within the motor output area have not been investigated. Utilizing advanced techniques, we demonstrate that lumbar astrocytes in a juvenile thoracic SCI mouse model switch to reactive phenotype, displaying morpho-functional and pro-inflammatory changes. These astrocytes also experience NBCe1-mediated intracellular acidosis, leading to Kir4.1 dysfunction and impaired K+ uptake. Enhancing Kir4.1 function reduces spasticity in SCI mice, revealing new therapeutic targets for neurological diseases associated with neuronal hyperexcitability. HighlightsO_LILumbar astrocytes adopt a reactive phenotype following a thoracic SCI C_LIO_LINBCe1-mediated acidosis in astrocytes disrupts Kir4.1 function post-SCI. C_LIO_LIImpaired K+ uptake leads to motoneuron hyperexcitability post-SCI. C_LIO_LIEnhanced astroglial Kir4.1 function reduces spastic-like symptoms in SCI mice. C_LI

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Barbay, T., Pecchi, E., Ramirez Franco, J. J., Ivanov, A., Brocard, F., Rouach, N., BOS, R.. 2024-10-12. Functional contribution of astrocytic Kir4.1 channels to spasticity after spinal cord injury. https://doi.org/10.1101/2024.10.11.617793

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