Abstracts

Rationale: Mutations of the KCNQ2 gene, which encodes the subunit of potassium channel KV7.2, can cause the risk of neonatal epilepsies such as benign familial neonatal epilepsy (BFNE) and early infantile epileptic encephalopathy type-7 (EIEE7). KV7.2 is a voltage-gated M-type potassium ion channel (M-channel). M-channels contribute to regulating action potential generation and exhibit inhibitory effects on the neurons of the telencephalon, including the hippocampus. The KCNQ2 mutations cause dysfunction in the M-channels and a subsequent hyper-excitability of neurons. Interestingly, the onset of BFNE and EIEE7 is restricted in the neonatal stage of development. It is known that GABA works as an excitatory neurotransmitter in the brain of the neonate. The excitatory action of GABA onto principal neurons could be a cause of epileptogenicity. Therefore, we hypothesized that the KCNQ2 mutations found in patients are related to abnormal GABA neurotransmitter systems in the neonatal period.Methods: To examine our hypothesis, we conducted electrophysiological studies using brain slice preparations from neonatal mice bred with Kcnq2 aa.Y284C mutation knock-in mice (Tomonoh et al., 2014) and VGAT-Venus transgenic mice (Wang et al., 2009). This study was approved by the ethical committee of Fukuoka University for the plan of genetically modified animal experiments and animal experimental designs.Results: In extracellular recordings, the spontaneous firing frequency of Venus positive GABAergic CA1 hippocampal neurons of mutant Kcnq2 mice was higher than that of wild-type (WT) mice (WT, n = 33, N = 7; Y284C/+, n = 42, N = 11; Y284C/ Y284C, n = 32, N = 6; χ22,104 = 4.93, p < 0.05 vs. WT, Kruskal-Wallis ANOVA, post hoc Steel-Dwass test). In whole-cell patch-clamp recordings, the frequency of spontaneous GABAergic postsynaptic currents of the CA1 pyramidal neurons of the mutant mice was higher than those of WT mice (WT, n = 23, N = 4; Y284C/+, n = 32, N = 7; Y284C/ Y284C, n = 13, N = 4; χ22,65 = 14.1, p < 0.05 vs. WT, Kruskal-Wallis ANOVA, post hoc Steel-Dwass test).Conclusions: Our results show that the Kcnq2 mutation facilitates the firing activity of GABAergic interneurons, and consequently increases GABA release on pyramidal neurons in the neonatal CA1 region of the hippocampus, suggesting a new cellular mechanism for neonatal epilepsies.