Kcnq2/Kv7.2 controls the threshold and bihemispheric symmetry of cortical spreading depolarization

Abstract

Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization associated with acute brain injury and migraine aura. Genetic studies link molecular defects in enhanced cytoplasmic Ca2+ flux, glial Na+-K+ ATPase, and interneuronal Na+ current with SD susceptibility, emphasizing the important roles of synaptic activity and extracellular ionic homeostasis in determining SD threshold. In contrast, gene mutations in ion channels that shape intrinsic membrane excitability are frequently associated with epilepsy susceptibility. It is not well known whether epileptogenic mutations in voltage-gated potassium channels that regulate membrane repolarization also modify SD threshold and generation pattern. Here we report that the Kcnq2/Kv7.2 potassium channel subunit, frequently mutated in developmental epilepsy, is an SD modulatory gene with significant control over seizure-SD transition threshold, bilateral cortical expression, and temporal susceptibility. Chronic DC-band cortical EEG recording from awake conditional Kcnq2 deletion mice (Emx2cre/+::Kcnq2flox/flox) revealed spontaneous cortical seizures and SD. In contrast to a related potassium channel deficient model, Kv1.1 KO mice, spontaneous cortical SDs in Kcnq2 cKO mice are tightly coupled to the terminal phase of seizures, arise bilaterally, and are observed predominantly during the dark phase. Administration of the nonselective Kv7.2 inhibitor XE991 to Kv1.1 KO mice reproduced the Kcnq2 cKO-like SD phenotype (tight seizure coupling and bilateral symmetry) in these mice, indicating that Kv7.2 currents directly and actively modulate SD properties. In vitro brain slice studies confirmed that Kcnq2/Kv7.2 depletion or pharmacological inhibition intrinsically lowers the cortical SD threshold, whereas pharmacological activators elevate the threshold to multiple depolarizing and hypometabolic SD triggers. Together these results identify Kcnq2/Kv7.2 as a distinctive SD regulatory gene, and point to SD as a potentially significant pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes. Our results also implicate KCNQ2/Kv7.2 channel activation as an adjunctive therapeutic target to inhibit SD incidence.