Ictal wavefront propagation in slices and simulations with conductance-based refractory density model.

Anton V Chizhov,Dmitry V Amakhin,Aleksey V Zaitsev,Elena Yu Smirnova,Maxim Bazhenov

doi:10.1371/journal.pcbi.1009782

Abstract

The mechanisms determining ictal discharge (ID) propagation are still not clear. In the present study, we aimed to examine these mechanisms in animal and mathematical models of epileptiform activity. Using double-patch and extracellular potassium ion concentration recordings in rat hippocampal-cortical slices, we observed that IDs moved at a speed of about 1 mm/s or less. The mechanisms of such slow propagation have been studied with a mathematical, conductance-based refractory density (CBRD) model that describes the GABA- and glutamatergic neuronal populations’ interactions and ion dynamics in brain tissue. The modeling study reveals two main factors triggerring IDs: (i) increased interneuronal activity leading to chloride ion accumulation and a consequent depolarizing GABAergic effect and (ii) the elevation of extracellular potassium ion concentration. The local synaptic transmission followed by local potassium ion extrusion and GABA receptor-mediated chloride ion accumulation underlies the ID wavefront’s propagation. In contrast, potassium ion diffusion in the extracellular space is slower and does not affect ID’s speed. The short discharges, constituting the ID, propagate much faster than the ID front. The accumulation of sodium ions inside neurons due to their hyperactivity and glutamatergic currents boosts the Na+/K+ pump, which terminates the ID. Knowledge of the mechanism of ID generation and propagation contributes to the development of new treatments against epilepsy.

Highlights

The exact nature of spatiotemporal dynamics of brain activity during seizures is of great importance
We showed that potassium ion diffusion can contribute to ictal discharge propagation; it leads to an ID propagation speed of much less than 0.1 mm/s
interictal discharges (IIDs) had a duration of about 1 s and, in some cases, transitioned to the IDs, which had the duration of 25–100 s and emerged every 5–10 min

Summary

Introduction

The exact nature of spatiotemporal dynamics of brain activity during seizures is of great importance. Several forms of SDs are distinguished: (i) predominantly, GABAergic interictal discharges (IIDs) emerging between IDs; (ii) IID-like preictal discharges (PIDs) that may take place just before an ID; and (iii) GABA-glutamatergic late short discharges (LSDs) that constitute either an ID in its late phase (known as intraictal bursts in [2]) or continuously repeating in status epilepticus. These discharges propagate through the brain tissue at different speeds. Whether the contribution of the ion dynamics into the ID propagation is direct—due to ion diffusion—or indirect—as a consequence of neuronal excitation—is still debated [22]

Objectives

Methods

Results

Discussion

Conclusion