Abstracts

Rationale: There are few abnormal patterns of neuronal activity as dramatic and obvious as epileptic seizures - one sees the abnormal activity reflected in the behavior and motor movements of the stricken subject. Mechanistically, we know little of how individual cells interact to form the observable patterns we call seizures. In most seizure models a shift from dominant inhibition to dominant excitation is considered to be responsible for the transition from the physiological to seizure state (Trevelyan, et al., 2006, J. Neurosci. 26: 12447). However, the cellular bases of such transition remain largely unknown. Here we present an ionic current model composed of Hodkin-Huxley type neurons aided by dynamic extracellular ion concentrations to investigate the interaction of excitatory and inhibitory neurons during seizure-like events. Methods: We model both cell types using two compartmental model (1) axo-somatic, and (2) dendritic compartments. The reversal potentials for various ion currents and leak conductances are updated based on instantaneous ion concentrations inside and outside the cells. The K⁺/Na⁺ concentration in the interstitial volume surrounding each cell was continuously updated based on K⁺/Na⁺ currents across the neuronal membrane, K⁺/Na⁺ pumps, uptake by the glial network surrounding the neurons, and lateral diffusion of K⁺ within the extracellular space. Results: We investigate the cellular mechanism for interaction between interneuron and pyramidal cell using compartmental model of two cells coupled through synaptic inputs and extracellular K⁺ diffusion. We observe that during the ictal discharges interneurons entered into depolarization block, while the pyramidal cell produced spike trains with increased frequency. The INs resumed their post-ictal spiking while PCs became progressively quiescent after this runaway excitation (see also Ziburkus, et al., 2006, J. Neurophysiol. 95:3948). We find that the lateral K⁺ diffusion in the extracellular space, the balance between inhibitory and excitatory synaptic strengths, and persistent sodium current play significant role in the cellular interaction during seizures. Conclusions: Through computational modeling we reach a framework that not only accurately reproduce the experimentally observed seizures but also demonstrates the interaction between inhibitory and excitatory neurons during seizures. We conclude that the extracellular diffusion of K⁺ ions and persistent sodium current play a major role in creating the interaction required to form seizures.