Cellular and network mechanisms of electrographic seizures

Epileptic seizures constitute a complex multiscale phenomenon that is characterized by synchronized hyperexcitation of neurons in neuronal networks. Recent progress in understanding pathological seizure dynamics provides crucial insights into underlying mechanisms and possible new avenues for the development of novel treatment modalities. Here we review some recent work that combines in vivo experiments and computational modeling to unravel the pathophysiology of seizures of cortical origin. We focus particularly on how activity-dependent changes in extracellular potassium concentration affect the intrinsic dynamics of neurons involved in cortical seizures characterized by spike/wave complexes and fast runs.

Introduction

It is widely accepted that the development of epileptiform activity can result from a shift in the balance between synaptic excitation and inhibition toward excitation [1, 2, 3, 4]. In fact, an easy way to elicit acute seizures experimentally is to block synaptic inhibition [5, 6, 7, 8, 9, 10, 11]. Accordingly, the traditional point of view is that the key intracellular correlate of epileptiform activity, the paroxysmal depolarizing shift (PDS), consists of a giant EPSP [12] enhanced by the activation of voltage-regulated intrinsic currents [1, 13, 14, 15, 16, 17]. It was therefore a surprise when more recent evidence showed that synaptic inhibition remains functional in many forms of paroxysmal activities [18, 19, 20, 21, 22, 23, 24, 25, 26]. Also, disruption of inhibitory function does not affect neocortical kindling [27], which is associated with an increase in synaptic strength that mediates recruitment of larger cortical areas [28]. Furthermore, the firing of fast-spiking inhibitory interneurons (INs) during cortically generated seizures is much stronger than the activity of other types of cortical neurons [24]. Therefore, a decrease or even the absence of synaptic inhibition in the presence of synaptic excitation cannot serve as a general mechanism of cortical epileptic seizures.

Extracellular potassium concentration [K⁺]_o increases during neuronal activity. In the presence of neuronal hyperexcitability, the [K⁺]_o apparatus fails to maintain [K⁺]_o homeostasis (Grafstain, [100]; Somjen, [101]; Frohlich, [102]). The resulting increase in [K⁺]_o depolarizes the reversal potential of K⁺ currents and can also affect the maximal conductances of some depolarizing currents such as the hyperpolarization-activated depolarizing current (I_h) [29] and the persistent sodium current (I_Na(p)) [30]. Thus, the overall effect of an increase in [K⁺]_o is an upregulation of neuronal excitability. Indeed, periodic bursting was found in vitro after increasing [K⁺]_o [31, 32, 33]. Thus, changes in [K⁺]_o may play a crucial role in seizure dynamics.

The complexity of the interaction dynamics between neuronal networks and ion concentrations during epileptiform activity requires a combined approach of experimental work and computational models. Here, we discuss recent modeling results regarding mechanisms of epileptic seizures in cortex. First, we present an analysis of the network and cellular mechanisms of electrographic seizures in vivo. Then, we discuss the results from computational models that incorporate extracellular K⁺ concentration dynamics based on experimental data. Our findings suggest that (1) changes in [K⁺]_o activate latent intrinsic burst dynamics that result in paroxysmal bursting and (2) the dynamic interaction between network activity and [K⁺]_o causes the emergence of a stable paroxysmal network state in the form of selfsustained oscillations. We conclude with specific predictions derived from our model and propose that molecular mechanisms responsible for [K⁺]_o regulation should be examined as novel targets for pharmacological intervention in patients suffering from epilepsy.