Focal astrocyte Kir4.1 loss drives seizures, spreading depolarizations and postictal impairments

Authors

Codadu, N. K., Gao, Y., Tyurikova, O., Dai, Z., Ban, X., Weng, Y., Masvidal-Codina, E., Garrido, J. A., Guimera-Brunet, A., Rusakov, D. A., Hashemi, K., Mazarakis, N. D., Wykes, R. C.

Abstract

Astrocytic dysfunction is increasingly recognised as an important contributor to epileptogenesis and seizure dynamics. Kir4.1 potassium channels expressed in astrocytes play a critical role in activity-dependent extracellular potassium buffering, and their loss may impair network stability and promote pathological hyperexcitability. In epilepsy, seizures can be accompanied by spreading depolarizations (SDs), propagating waves of neuronal and glial depolarization. While seizure-associated SDs have been proposed to terminate seizures and limit seizure spread, they have also been implicated in postictal dysfunction and sudden unexpected death in epilepsy (SUDEP), and their significance in chronic epilepsy remains unclear. Here, we tested whether focal loss of astrocytic Kir4.1 in the adult hippocampus is sufficient to disrupt potassium buffering, generate spontaneous seizures, and promote seizure-associated SDs. Using astrocyte-targeted viral vector Cre recombinase in adult Kir4.1-floxed mice, we induced focal hippocampal reduction of Kir4.1 expression. This impaired activity-dependent potassium buffering, producing enhanced stimulation-evoked extracellular potassium accumulation and larger DC shifts in hippocampal slices. Chronic wireless EEG recordings demonstrated that focal astrocytic Kir4.1 loss was sufficient to induce spontaneous recurrent seizures and interictal epileptiform activity. To investigate seizure-associated SDs, we combined optogenetic stimulation with graphene-based micro-transistor recordings capable of stable full-bandwidth DC electrophysiology in awake head-fixed mice. Focal hippocampal loss of astrocytic Kir4.1 markedly increased susceptibility to evoked seizures accompanied by SDs. We used chronic wireless DC-coupled video-telemetry recordings to continuously monitor seizure and SD dynamics in freely moving mice. SDs occurred frequently during generalized seizures and were first detected in cortical channels. Seizures accompanied by SDs exhibited greater spectral power, longer duration, and prolonged postictal depression compared with seizures alone. Behaviourally, seizures accompanied by SDs were linked to postictal impairment characterised by behavioural arrest and abnormal motor behaviours. These findings highlight the utility of graphene micro-transistor arrays and chronic DC-coupled telemetry for resolving infraslow (<0.1 Hz) epileptic dynamics that are largely inaccessible using conventional electrophysiological approaches. Ground-truth DC-coupled recordings enabled identification of AC-band electrographic signatures that segregated seizures with SDs from seizures alone, raising the possibility that SD-associated seizures may be retrospectively inferred from conventional AC-coupled epilepsy datasets. We demonstrate that focal astrocytic Kir4.1 loss in the adult brain impairs potassium buffering and is sufficient to drive spontaneous seizures, supporting astrocytic potassium dysregulation as a determinant of seizure and spreading depolarization susceptibility in epilepsy. Furthermore, seizure-associated SDs are strongly linked to increased postictal impairments, supporting the concept that SDs are major determinants of pathological postictal states.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 20 Jun 2026.

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