ArticleGene therapy2026
Local targeted suppression of neocortical spreading depolarization amplitude by viral expression of KCa3.1 channels.
Article in Gene therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Cortical spreading depolarization (SD) underlies migraine, frequently co-occurs with seizures, and is associated with poor prognosis after stroke. In rodent models, most genetic therapies for epilepsy suppress seizures by enhancing neuronal K⁺ conductance. Although seizures and SD often co-occur and SD causes temporary neuronal silencing, it remains unknown whether K⁺-conductance-enhancing gene therapy affects SD. Here, we present a genetic method for targeted downregulation of SD using adeno-associated virus to express KCNN4, which encodes the Ca²⁺-gated KCa3.1 channels. We tested the effect of KCNN4 expression in rodent neocortex using patch-clamp electrophysiology, functional imaging in brain slices, and field potential recording in vivo. KCNN4 expression reduced acute seizure-like activity, lowered SD amplitude several-fold both in vivo and in vitro, and slowed SD propagation in brain slices, where epileptiform activity paradoxically reappeared faster after SD. Moreover, SD triggered a Ca²⁺ rebound upon restoration of epileptiform activity, which was counterbalanced by KCa3.1-mediated afterhyperpolarization. Targeted suppression of SD amplitude using KCNN4 expression provides a proof-of-principle for potential gene therapy models for disorders complicated by SD. Reducing SD via increased neuronal K⁺ conductance may have a side effect worth considering in gene therapy for epilepsy, as some literature suggest that SD itself may terminate seizures.
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