Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy

We show here that the voltage-gated K+ channel Kv12.2 is a potent regulator of excitability in hippocampal pyramidal neurons. Genetic deletion and pharmacologic block of Kv12.2 significantly reduced firing threshold in these neurons. Kv12.2−/ − mice displayed signs of persistent neuronal hyperexcitability including frequent interictal spiking, spontaneous seizures and increased sensitivity to the chemoconvulsant pentylenetetrazol. Hippocampal and cortical hyperexcitability is a defining feature of most epilepsies1, 2. The molecular mechanisms regulating excitability in these brain regions are not fully understood, but genetic studies have revealed a critical role for sub-threshold voltage-gated K+ currents, which are in part encoded by Kv7 (KCNQ)–based M-channels3. We therefore reasoned that Kv12.2 (KCNH3, Elk2), which is highly expressed in hippocampal and cortical pyramidal neurons4, could also significantly contribute to the control firing because of its hyperpolarized voltage-activation range5, 6 (Supplementary Fig. 1). Kv12 channels have been highly conserved since the beginnings of the metazoan lineage, implying an important and non–redundant physiological function. They are present in the genomes of the earlies