Barbay, T. | Search bioRxiv

bioRxiv2024

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

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

neuroscience↗

bioRxiv2022

Astrocytes regulate locomotion by orchestrating neuronal rhythmicity in the spinal network via potassium clearance

SO_SCPLOWUMMARYC_SCPLOWNeuronal rhythmogenesis in the spinal cord is correlated with variations in extracellular K+ levels ([K+]e). Astrocytes play important role in[K+]e homeostasis and compute neuronal information. Yet it is unclear how neuronal oscillations are regulated by astrocytic K+ homeostasis. Here we identify the astrocytic inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) as a key molecular player for neuronal rhythmicity in the spinal central pattern generator (CPG). By combining two-photon calcium imaging with electrophysiology, immunohistochemistry and genetic tools, we report that astrocytes display Ca2+ transients before and during oscillations of neighbouring neurons. Inhibition of astrocytic Ca2+ transients with BAPTA decreases the barium-sensitive Kir4.1 current responsible of K+ clearance. Finally, we show in mice that Kir4.1 knockdown in astrocytes progressively prevents neuronal oscillations and alters the locomotor pattern resulting in lower motor performances in challenging tasks. These data identify astroglial Kir4.1 channels as key regulators of neuronal rhythmogenesis in the CPG driving locomotion. SO_SCPLOWIGNIFICANCEC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWSTATEMENTC_SCPLOWDespite decades of research, the cellular mechanisms responsible of the synchronized rhythmic oscillations driving locomotion remain elusive. To gain insight into the function of the spinal locomotor network, numerous studies have characterized diverse classes of locomotor-related neurons to determine their role in generating rhythmic movements during locomotion. In contrast, studies investigating non-neuronal components of the spinal cord are sparse. Our study represents a significant breakthrough by identifying astrocytic K+ uptake as a key regulator of neuronal rhythmicity synchronization and locomotor pattern at the cellular, microcircuit and system levels. These data provide mechanistic insights into the neuroglial dialogue at play during rhythmogenesis and point to a novel astroglial target for restoring normal neuronal network excitability in brain disorders and neurodegenerative diseases.

neuroscience↗