Role of astrocytes in the clearance of excess extracellular potassium

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Abstract

The development of concepts describing potassium clearance mechanisms in the mammalian central nervous system in the last 35 years is reviewed. The pattern of excess potassium in the extracellular space is discussed as are the implications of these potassium levels for neuronal excitability. There is a systematic description of the available evidence for astrocytic involvement in situ. The three possible astrocytic potassium clearance mechanisms are introduced: spatial buffer mechanism; carrier-operated potassium chloride uptake as well as channel-operated potassium chloride uptake. The three mechanisms are compared and their compatibility is discussed. Evidence is now available showing that at least two of these if not all three mechanisms co-exist and complement each other. Finally, it is concluded that these potassium movements are not used as a signal system, only as a homeostatic feedback mechanisms. Such a genuine signal system involving glial elements exists — but it is based on calcium waves.

Introduction

During neuronal activity, potassium ions are transferred from the cytoplasm to the extracellular space (ECS). It has been shown that neuronal re-uptake and diffusion in the ECS are too slow to prevent a build-up of potassium that affects synaptic transmissions and axonal ion channel kinetics. Hertz (1965) was the first to postulate that astrocytes are involved in this potassium clearance of the extracellular space and moreover, suggested that astrocytes could use the manipulation of the extracellular potassium concentration as a means to control neuronal excitability. Since then more information on this interaction was collected and the role of astrocytes is now, together with transmitter removal, one of the well established roles of astrocytes in situ.

Section snippets

Extracellular potassium levels in the CNS

The most often used method of estimating increases in the extracellular potassium concentration is the use of potassium-sensitive double-barreled microelectrodes. This method is accurate enough for the estimation of wide-spread or massive potassium release. However, release by point sources will be underestimated. This is due to the creation of a dead space around the tip of the electrode that is several times the magnitude of the extracellular space. Therefore any limited amount of potassium

Effect of excess extracellular potassium on neuronal processing

There is only a need for potassium homeostasis if values of excess potassium in the range as encountered above are able to significantly change the excitability of neurons. That such is the case has been shown repeatedly. These concentrations affect transmitter release (Erulkar and Weight, 1977, Gage and Quastel, 1965) and electrical properties of axons (Malenka et al., 1981). More specifically, it was shown that increases of the extracellular potassium concentration to 5 mM change the action

Astrocytes as the site of potassium regulatory mechanisms

One would expect that immediate re-uptake of potassium into neurons and diffusion in the extracellular space would be sufficient to prevent a build-up of excess extracellular potassium. There must be potassium removal sites not resident in neurons, because iontophoretically applied extracellular potassium is removed as efficiently as the potassium that was released from the neurons. Only in the second case would there be simultaneous accumulation of neuronal sodium that would stimulate the

The spatial buffer concept

This concept was first advanced by Orkand et al. (1966) on the basis of their experiments with giant glial cells in the leech CNS. It assumes a glial syncytium in which extracellular potassium is increased in one region. In a syncytium, the membrane of neighboring cells has a tendency to stay isopotential. Therefore the region experiencing an increased extracellular potassium concentration will have a potassium equilibrium potential that is more positive than the membrane potential. This will

Astrocytes as transient storage sites for potassium

The operation of the spatial buffer current requires no storage of potassium ions: for every potassium ion entering the syncytium, one is leaving at the same time, although at a different location. Thus no significant accumulation of potassium inside astrocytes will take place and any observed accumulation can be seen as an indication of a mechanism other than spatial buffering being active. In all preparations tested, astrocytes accumulate potassium ions when the extracellular potassium

Modification of properties involved in potassium clearance

During neuronal activity, factors other than potassium are changed in the extracellular space, with one of the most important being the volume of this space (Ransom, 1992). In turn many of the processes involved in astrocytic clearing of potassium-like channel conductances, carrier activity and gap junction conductance are modulated by those factors. Examples are the increases of intracellular calcium in astrocytes that in turn causes the activation of calcium-dependent potassium channels (

Potassium as a signal

The original concept as advanced by Hertz (1965) went beyond the role of astrocytes as purely homeostatic satellite cells in proposing that the uptake, storage and subsequent selective release of potassium might be purposefully used to change neuronal excitability. In this way Hertz proposed a novel signal system in the brain. Now almost 35 years later is more evidence for this concept available? There is evidence that exposure to elevated potassium of cultured astrocytes or loading of

Conclusions

The involvement of astrocytes into potassium clearance can be taken as an established fact. What is still open to debate is how these three potential mechanisms, spatial buffer loops, carrier-operated KCl accumulation and channel-operated KCl accumulation co-exist and complement each other. More information is needed from functional modules to find which excitation patterns and pathological events in neurons are evoking what kind of specific response of the glial syncytium. It is quite clear,

Acknowledgements

The author is presently funded by operating grants from the Medical Research Council of Canada.

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