Kcnq2/Kv7.2 controls the threshold and bi-hemispheric 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 depolarizing molecular defects in Ca2+ flux, Na+ current in interneurons, and glial Na+-K+ ATPase with SD susceptibility, emphasizing the important roles of synaptic activity and extracellular ionic homeostasis in determining SD threshold. In contrast, although gene mutations in voltage-gated potassium ion channels that shape intrinsic membrane excitability are frequently associated with epilepsy susceptibility, it is not known whether epileptogenic mutations that regulate membrane repolarization also modify SD threshold and propagation. 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 the seizure-SD transition threshold, bihemispheric cortical expression, and diurnal temporal susceptibility. Chronic DC-band cortical EEG recording from behaving conditional Kcnq2 deletion mice (Emx1cre/+::Kcnq2flox/flox) revealed spontaneous cortical seizures and SD. In contrast to the 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 Kv7.2 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 a potential adjunctive therapeutic target to inhibit SD incidence.

Mouse models of Kcnq2 dysfunction

“…In addition to proving that Kcnq2 is required for M‐channel activity from the embryonic stages, this study showed an increased transcription of the Kcnq3 and Kcnq5 genes, suggesting a compensatory mechanism following the loss of Kcnq2 expression 22 . Recently, several models with Kcnq2 deletion restricted to cortical pyramidal neurons and CA1 excitatory and inhibitory neurons were produced 23‐26 . They showed that Kcnq2 is required to regulate neuronal excitability through cortical spreading depolarization regulation, the increase of input resistance, action potential number, and medium afterhyperpolarization (mAHP) in pyramidal neurons 23‐25 .…”

The effects of certain TRP channels and voltage-gated KCNQ/Kv7 channel opener retigabine on calcitonin gene-related peptide release in the trigeminovascular system

“…Kv7.2 and Kv7.3 of Kv7 channels are predominantly expressed in trigeminovascular system (8–10). Additionally, in the study mentioned above (29) it was demonstrated that Kv7.2 channel activation inhibited the CSD. We therefore speculate that retigabine may exert its CGRP-reducing effects substantially through activation of Kv7.2 and/or Kv7.3.…”

KCNQ2 and KCNQ5 form heteromeric channels independent of KCNQ3

“…3 B ). Importantly, knockin mice carrying the KCNQ2 3XFLAG epitope were viable, with no evidence of increased lethality or behavioral seizures, which occur in animals with reduced KCNQ2 channel activity ( 14 , 33 , 34 ). Additionally, births followed a Mendelian distribution when heterozygous Kcnq2 flag/+ mice were bred together (18 wild-type: 25.7%; 32 heterozygous: 45.7%; 20 homozygous: 28.6%), consistent with normal KCNQ2 function.…”