4-Aminopyridine induced hyperpolarizing oscillations in pediatric human epileptic tissue are network-driven potassium currents that are abolished by activation of KCNQ2–5 (Kv7.2-Kv7.5) channels

TL;DR

This study shows that potassium fluctuations in epileptic brain tissue cause hyperpolarizing oscillations, which can be stopped by activating specific potassium channels.

Contribution

The study identifies network-driven potassium currents as a novel mechanism for hyperpolarizing oscillations in epileptic tissue.

Findings

4-aminopyridine induces hyperpolarizing oscillations in human epileptic neocortex.

Hyperpolarizing oscillations are dependent on network activity and abolished by KCNQ2–5 channel activation.

Calcium plays a role in KCNQ channel activation and potassium fluctuation stabilization.

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 GABAA/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.

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