Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 43

The effect of extracellular potassium is multi-faceted. Sustained potassium efflux increases extracellular potassium concentration, depolarizing the membrane and moving the intra-cellular voltage toward the threshold for sodium action potential firing. As extracellular potassium continues to accumulate, there is membrane depolarization and action potential firing increases. With further accumulation, the membrane potential becomes more depolarized than the firing threshold for sodium-action potentials, sodium channels inactivate, and neuronal firing ceases. In vitro experiments by Bikson et al. (2003) illustrate these effects of extracellular potassium accumulation. Electrographic seizure-like activity triggered in hippocampal slices by exposure to low-calcium artificial cerebro-spinal fluid (aCSF) manifested as recurrent periods of population firing followed by periods of electrographic silence lasting 12–18 s. The termination of each electrographic discharge by a period of electrographic silence resulted from transient increases in extracellular potassium to plateaus of approximately 12 mM. The depolarized state was maintained by the elevation of extracellular potassium and by the presence of persistent sodium channels that did not inactivate. Depolarization blockade-terminating seizure-like discharges have also been observed in neocortical slices in which GABA-ergic inhibition is partially blocked by picrotoxin (Pinto et al., 2005). Focal or localized increases in potassium may also trigger additional potassium release beyond the initial region of potassium accumulation. Shifts in extracellular potential, and oscillations seen at the end of hippocampal after-discharges, have been attributed to a rapid rise in extracellular potassium that triggers waves of astrocyte depolarization and a propagating rise in potassium that terminates neuronal firing (Bragin et al., 1997). In addition to its direct depolarizing effects, increased extracellular potassium may also indirectly result in membrane depolarization through the action of the potassium–chloride co-transporter KCC2. The rise in extracellular potassium can increase intracellular chloride, shifting the chloride reversal potential toward membrane depolarization. In the setting of increased intracellular chloride, the action of GABA to open chloride channels could enhance membrane depolarization to the point of becoming refractory to further firing of action potentials (Jin et al., 2005; Galanopoulou, 2007).

Extracellular calcium levels also change markedly during paroxysmal neuronal firing and may affect the efficiency of neuron-to-neuron spread of activity. Focal seizure activity results in a decline in extracellular calcium activity of approximately 50% (Heinemann et al., 1977). This decline may inhibit synaptic transmission because synaptic vesicle fusion and neurotransmitter release are dependent on entry of extracellular calcium (King et al., 2001; Cohen and Fields, 2004). Decline in extracellular calcium also potentially affects gap junction function as hemichannel opening increases in low calcium (Thimm et al., 2005).