Simulated Seizures and Spreading Depression in a Neuron Model Incorporating Interstitial Space and Ion Concentrations

Abstract

Sustained inward currents in neuronal membranes underlie tonic-clonic seizure discharges and spreading depression (SD). It is not known whether these currents flow through abnormally operating physiological ion channels or through 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,T) and I(Na,P)), potassium currents (I(K,DR) and I(K,A)), and N-methyl-D-aspartate (NMDA) receptor-controlled currents (I(NMDA)), were inserted in the appropriate regions of the model cell. The neuron was surrounded by an interstitial space where extracellular potassium and sodium concentration ([K(+)](o) and [Na(+)](o)) could rise or fall. Changes in intra- and extracellular ion concentrations and the resulting shifts in the driving force for ionic currents were continuously computed based on the amount of current flowing through the membrane. A Na-K exchange pump operated to restore ion balances. In addition, extracellular potassium concentration, [K(+)](o), was also controlled by a "glial" uptake 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 evoked repetitive firing that ceased when the stimulating current stopped. If, however, [K(+)](o) was allowed to rise, then a brief pulse provoked firing that outlasted the stimulus. At the termination of such a burst, the cell hyperpolarized and then slowly depolarized and another burst erupted without outside intervention. Such "clonic" bursting could continue indefinitely maintained by an interplay of the rise and fall of potassium and sodium concentrations 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 both I(NMDA) and I(Na,P) were present, the two acted synergistically. We conclude that epileptiform neuronal behavior and SD-like depolarization can be generated by the feedback of ion currents that change ion concentrations, which, in turn, influence ion currents and membrane potentials. The normal stability of brain function must depend on the efficient control of ion activities, especially that of [K(+)](o).

Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

“…Epilepsy was long thought to be primarily caused by malfunction of neurons, but in the last decades many studies have convincingly shown that alterations in astrocyte function play an important role in its pathogenesis 43, 53. In line with this, our study demonstrates that loss of function of the astrocyte‐specific protein MLC1 leads to dysregulation of [K + ] o , network hyperexcitability and seizures.…”

“…It is well established that astrocytes are crucial for [K + ] o homeostasis 13, 14. Mathematical models show that disturbing glial K + uptake can lead to seizures,43 and dysfunctional astrocyte [K + ] o homeostasis is implicated in epilepsy 44. K + homeostasis is tightly linked to the homeostasis of other ions, and MLC1 and GlialCAM colocalize and/or interact with several proteins involved in ion and water homeostasis.…”

Calcium sensitive non-selective cation current promotes seizure-like discharges and spreading depression in a model neuron

“…The morphology of the computer model used here is similar to the one described in Kager et al (2000Kager et al ( , 2002Kager et al ( , 2007 as the "simplified" cell, and it is illustrated in Kager et al (2007).…”

“…Ionic pumps were implemented that exchanged 3 Na + for 2 K + , that exchanged 3 Na + for 1 Ca 2+ and ones that extruded Ca 2+ , all under the assumption of unlimited energy. (See Kager et al 2000and Somjen et al 2008 for details).…”

“…Earlier we have simulated seizure-like and SD-like processes (Kager et al 2000(Kager et al , 2002(Kager et al , 2007Somjen et al 2008) in a neuron model based on the NEURON simulation environment of Hines, Moore and Carnevale (Hines and Carnevale 1997). It appeared that SD and HSD could be simulated in the presence of either a persistent Na + current (I Na,P ) or one that resembled NMDA-controlled current (I NMDA ).…”