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

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 K+ uptake to reduce spasticity following spinal cord injury (SCI). Astrocytes buffer extracellular K+ via Kir4.1 channels, preventing neuronal hyperexcitability. Following 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. We here demonstrate that lumbar astrocytes in a juvenile thoracic SCI mouse model switch to a reactive phenotype, displaying morpho-functional and pro-inflammatory changes. These astrocytes also experience electrogenic sodium bicarbonate cotransporter 1 (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.

Keywords: NBCe1 transporter; astrocyte targeting therapy; astrocytic acidosis; neuronal hyperexcitability; potassium homeostasis; reactive astrocyte.