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The Journal of Neurophysiology Vol. 84 No. 1 July 2000, pp. 495-512
Copyright ©2000 by the American Physiological Society
1Institute of Neurobiology, University of Amsterdam, 1098 SM Amsterdam, The Netherlands; and 2Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710
Kager, H.,
W. J. Wadman, and
G. G. Somjen.
Simulated Seizures and Spreading Depression in a Neuron Model
Incorporating Interstitial Space and Ion Concentrations. J. Neurophysiol. 84: 495-512, 2000. 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 (INa,T and
INa,P), potassium currents
(IK,DR and IK,A),
and N-methyl-D-aspartate (NMDA)
receptor-controlled currents (INMDA), 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, INa,P. When both
INMDA and INa,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.
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