Abstract
Epilepsy is one of the most common neurological disorders worldwide. Despite the availability of many anti-seizure medicines (ASMs), about 30 % of patients with epilepsy develop drug-resistant epilepsy. Unfortunately, the mechanisms of ictogenesis in patients with drug-resistant epilepsy remain to be elucidated. Here, we used 4-aminopyridine (4-AP) to study interictal-like oscillations in human epileptic neocortex. 4-AP is a voltage-gated potassium channel blocker commonly used to induce seizure-like activity in ex vivo brain slices. We observed that 4-AP induced neuronal bursting and robust slow, hyperpolarizing oscillations (HypOs) in layer 2/3 (L2/3) pyramidal neurons (PNs). Using paired recordings, we demonstrate that neuronal bursting and HypOs are synchronized between neighboring L2/3 PNs. We also determined that 4-AP-induced HypOs are potassium currents that were not mediated by GABA(A)/(B) receptors, NMDA receptors or AMPA receptors, or NKCC1 and KCC2 channels. Instead, HypOs are dependent on network activity and are impacted by gap junction blockade. Interestingly, HypOs were eliminated by activation, but not inactivation, of KCNQ2-5 (Kv7.2-Kv7.5) channels and were reduced via intercellular calcium chelation suggesting a role for calcium in KCNQ channel activation. Our results indicate 4-AP-induced HypOs are due to GABAergic interneuron synchronization, which leads to local extracellular potassium fluctuations without the need for GABA neurotransmission. Moreover, KCNQ2-5 channel activation can help stabilize potassium fluctuations, resulting in cessation of interictal-like events.