Spreading depression is associated with a nearly complete depolarization of neurons and glial cells and loss of neural excitability and synaptic transmission that spreads within neural tissue at a velocity of a few millimeters per minute. It can be triggered by mechanical, chemical and thermal stimuli as well as oxygen withdrawal.

Spreading depression

In response to hypoxia central neurons respond either with a moderate depolarization or hyperpolarization, depending on whether the net response of the hypoxia-induced currents is inwardly or outwardly directed. Depending on the vulnerability of the cell type affected, the initial response is followed within a few minutes by a massive and nearly complete depolarization also termed "anoxic depolarization" or "terminal depolarization".

In the hippocampal CA1 region this massive depolarization occurs within a few minutes of severe hypoxia. Due to its high degree of synchronization within the neuronal population, the massive depolarization causes a negative shift of the extracellular DC potential (hypoxia-induced spreading depression) by as much as -20 mV which is spreading over wide areas of the hippocampus.

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Anoxic depolarization of a CA1 pyramidal neuron and associated changes in extracellular DC potential and interstitial [K+].
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Spreading depression is also accompanied by characteristic changes in light scattering. Those tissue sections being invaded by SD show an increase in light scattering, i.e. an increased reflectance of light. As a result the tissue appears brighter. The very origin of these intrinsic optical changes is only partially understood. Though strictly being Cl- dependent, cell volume changes contribute only to a minor degree to the generation of these optical signals. Possibly, cytoarchitectural changes play a role.

Intrinsic optical signal in an hippocampal slice (frame rate is 2.5s /frame)

Spreading depression is not the result of a general loss of membrane integrity or selective permeability, nor the activation of an obscure "mega-channel". It rather reflects the concerted activation of various ion channels mediating the massive influx of Na+ and Ca2+ into neurons and K+ efflux into the extracellular space. The parallel rather than sequential organization of the contributing mechanisms explains, why spreading depression cannot be blocked by inhibition of only one channel type; the other channels just take over, and once triggered, allow spreading depression to appear in an all-or-none-fashion.

Flowchart summarizing the events and ionic pathways contributing to the generation of spreading depression