Spreading depression

The spreading depression of electric activity in the cerebral cortex, initially described by Aristide Leao in 1944, is a wave of cellular depolarization, which travels through the grey matter at a velocity of about 1.5 to 7.5mm/min. This propagating wave of depolarization can be triggered by local massive increases in extracellular K+ concentration and/or glutamate, which are the consequences of exaggerated focal electrical activity or mechanical or ischaemic injury. The most striking features of spreading depression are the rapid propagating elevation of extracellular K+ concentration up to 80 mM; a dramatic (~10 times) decrease in extracellular Ca2+ concentration and propagating shrinkage of the extracellular space by up to 50 per cent. These changes have complex kinetics, and begin with an initial slight elevation in extracellular K+, which is followed by a regenerative steep increase in [K+]o, decrease in [Ca2+]o and shrinkage of the extracellular space. During this period of excessive rise in [K+]o, Na+, Ca2+ and Cl- ions enter the cells, which rapidly eliminates neuronal excitability. In the meantime, astroglial cells become alkaline, most likely due to the activity of bicarbonate transporter. Elevation of extracellular K+ concentration lasts for one to two minutes, after which the cells repolarize, and all ion gradients are normalized (the recovery period). Neurones regain their excitability within the subsequent three to five minutes, and the whole wave of spreading depression can be repeated after another 10 minutes (which reflects the refractory period). Spreading depression waves in normal tissue do not result in any cell damage, although repetitive incidences of spreading depression may activate microglia and induce reactive astrogliosis in its mild form; both processes seem to be fully reversible. In conditions of brain ischaemia, however, spreading depression may increase the area of cellular damage (see Chapter 10.3).

There is much evidence linking the development of spreading depression with astroglial networks; particularly important are the demonstration of the effective inhibition of spreading depression by pharmacological inhibition of gap junctions and the discovery of circulating currents passing through the glial syncytium during a course of spreading depolarization. An apparent similarity between propagating astroglial calcium waves and the propagation of spreading depression led to a hypothesis of a triggering role for the former; this remains controversial, however; as in mouse neocortex, for example, it was possible to pharmacologically dissociate astroglial calcium waves and spreading depression. Nonetheless, the leading role played by astrocytes in the development of spreading depression remains firm; although the underlying mechanisms require further elaboration. The pathological potential of spreading depression also requires further attention; at present it is implicated in the developments of migraine and brain ischaemic damage.

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