Simulated seizures and spreading depression in a neuron model incorporating interstitial space and ion concentrations

Sustained inward currents in neuronal membranes underlie tonic-clonic seizu re discharges and spreading depression (SD). It is not known whether these currents flow through abnormally operating physiological ion channels or th rough pathological pathways that are not normally present. We have now used the NEURON simulating environment of Hines, Moore, and Carnevale to model seizure discharges and SD. The geometry and electrotonic properties of the model neuron conformed to a hippocampal pyramidal cell. Voltage-controlled transient and persistent sodium currents (I-Na,I-T and I-Na,I-P), potassium currents (I-K,I-DR and I-K,I-A), and N-methyl-D-aspartate (NMDA) receptor- controlled currents (I-NMDA), were inserted in the appropriate regions of t he model cell. The neuron was surrounded by an interstitial space where ext racellular potassium and sodium concentration ([K+](o) and [Na+](o)) could rise or fall. Changes in intra- and extracellular ion concentrations and th e resulting shifts in the driving force for ionic currents were continuousl y computed based on the amount of current flowing through the membrane. A N a-K exchange pump operated to restore ion balances. In addition, extracellu lar potassium concentration, [K+](o), was also controlled by a "glial" upta ke function. Parameters were chosen to resemble experimental data. As long as [K+](o) was kept within limits by the activity of the Na-K pump and the "glial" uptake, a depolarizing current pulse applied to the cell soma evoke d repetitive firing that ceased when the stimulating current stopped. If, h owever, [K+](o) was allowed to rise, then a brief pulse provoked firing tha t outlasted the stimulus. At the termination of such a burst, the cell hype rpolarized and then slowly depolarized and another burst erupted without ou tside intervention. Such "clonic" bursting could continue indefinitely main tained by an interplay of the rise and fall of potassium and sodium concent rations with membrane currents and threshold levels. SD-like depolarization could be produced in two ways, 1) by a dendritic NMDA-controlled current. Glutamate was assumed to be released in response to rising [K+](o). And 2) by the persistent (i.e., slowly inactivating) Na-current, I Na, P. When bot h I-NMDA and I-Na,I-P were present, the two acted synergistically. We concl ude that epileptiform neuronal behavior and SD-like depolarization can be g enerated by the feedback of ion currents that change ion concentrations, wh ich, in turn, influence ion currents and membrane potentials. The normal st ability of brain function must depend on the efficient control of ion activ ities, especially that of [K+](o).