Abstract
The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG), a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB), which is the first-line antiepileptic drug for seizures in neonates. The subjects were heterozygous knock-in mice (Kcnq2Y284C/+ and Kcnq2A306T/+) bearing the Y284C or A306T Kcnq2 mutation, respectively, and their wild-type (WT) littermates, at 63–100 days of age. Seizures induced by intraperitoneal injection of kainic acid (KA, 12mg/kg) were recorded using a video-electroencephalography (EEG) monitoring system. Effects of RTG on KA-induced seizures of both strains of knock-in mice were assessed using seizure scores from a modified Racine’s scale and compared with those of PB. The number and total duration of spike bursts on EEG and behaviors monitored by video recording were also used to evaluate the effects of RTG and PB. Both Kcnq2Y284C/+ and Kcnq2A306T/+ mice showed significantly more KA-induced seizures than WT mice. RTG significantly attenuated KA-induced seizure activities in both Kcnq2Y284C/+ and Kcnq2A306T/+ mice, and more markedly than PB. This is the first reported evidence of RTG ameliorating KA-induced seizures in knock-in mice bearing mutations of Kcnq2, with more marked effects than those observed with PB. RTG or other Kv7.2-channel openers may be considered as first-line antiepileptic treatments for epilepsies resulting from KCNQ2 mutations.
Highlights
Kv7.2/Kv7.3, a hetero-tetrameric voltage-gated potassium channel, consists of two types of subunits, which are encoded by KCNQ2 and KCNQ3
A recent line of evidence shows that some KCNQ2 mutations cause early onset epileptic encephalopathies (EOEEs) or early infantile epileptic encephalopathies (EIEE), such as Ohtahara syndrome [8,9,10,11,12], which are associated with intractable seizures followed by profound psychomotor delay
The differences in the distribution of the seizure score between the mutant and WT mice and between the two strains of mutant mice were statistically significant (p = 0.0002, Kcnq2Y284C/+ vs. WT; p = 0.0024, Kcnq2A306T/+ vs. WT; p = 0.0982, Kcnq2Y284C/+ vs. Kcnq2A306T/+), as assessed by the logistic regression analysis. These results indicate that Kcnq2Y284C/+ and Kcnq2A306T/+ mice have significantly higher sensitivity to kainic acid (KA)-induced seizures than WT mice, and Kcnq2Y284C/+ mice have higher sensitivity to KA-induced seizures than Kcnq2A306T/+ mice
Summary
Kv7.2/Kv7.3, a hetero-tetrameric voltage-gated potassium channel, consists of two types of subunits, which are encoded by KCNQ2 and KCNQ3. Kv7.2/Kv7.3 is predominantly expressed in the hippocampus, neocortex, and the granular layer of the cerebellum [1,2,3,4] and generates the neuronal M-current, which stabilizes the membrane potential and controls neuronal excitability. Kv7.2/Kv7.3 plays an important role in limiting network excitability in the neonatal brain, where GABAergic action is depolarizing and excitatory [5]. Mutations in KCNQ2 and KCNQ3 are known to cause predominantly benign familial or non-familial neonatal epilepsy (BFNE or BNE) [2,6,7], both of which remit spontaneously in late infancy and are self-limited. Most individuals with BFNE or BNE have a benign course; some patients may have varying degrees of developmental delays and epilepsy recurring later in their life [11,12]. The development of rational therapy for epilepsies caused by dysfunctions resulting from mutated Kv7.2/Kv7.3 is urgently needed
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