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Spreading depression (SD), a neuronal mechanism involved in brain pathophysiology, occurs in brain areas with high neuronal density such as the cerebral cortex. By contrast, the brain stem is thought to be resistant to SD. Here we show that DC shifts resembling cortical SD can be elicited in rat brain stem by topical application of KCl but not by pricking the brain stem. However, this was only possible until postnatal day 13, and, in addition, susceptibility for SD had to be enhanced. The latter was achieved by superfusion of the brain stem for 45 min with a solution containing acetate instead of chloride ions. Transient asphyxia or hypoxia by 2 min breathing 6% O2 in N2 had a similar effect. Negative brain stem DC deflections were paralleled by an increase of extracellular potassium concentration

Cortical spreading depression is a pathophysiological excitation wave that occurs during pathophysiological brain conditions such as ischemic brain infarction, migraine aura, and others. Judged from experiments in rodents, the brainstem is thought to be comparatively resistant to the generation of spreading depression. However, because spreading depression can be elicited in the brainstem of rat pups after superfusing the brainstem with solutions enhancing excitability, we reinvestigated spreading depression in the brainstem of the adult rat. Based on theoretical predictions indicating a major role of extracellular potassium in susceptibility to spreading depression, we used conditioning solutions in which chloride ions were replaced by acetate and tetraethylammonium chloride and a small amount of KCl were added. Under these conditions, spreading depression was reproducibly elicited in the brainstem either by topical application of KCl crystals to the brainstem surface or by local microinjection of KCl into the brainstem. The direct current shifts so elicited were accompanied by typical elevation of extracellular potassium ions, propagated in the brainstem, and were prevented by MK-801, an N-methyl D-aspartate blocker. During spreading depression, the regional blood flow in the brainstem was transiently increased. In addition, systemic arterial blood pressure, but not the heart rate, was transiently enhanced. In the nonconditioned brainstem, KCl stimulation neither elicited spreading depression nor induced changes in regional blood flow and blood pressure. These data show that proper conditioning renders the brainstem susceptible to spreading depression, and that spreading depression at this site elicits changes in local circulation and systemic blood pressure.

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We identified a functional link between TNF and CSD. TNF activates TNFR2 in cortical inhibitory interneurons. The resulting release of GABA reduces CSD amplitudes. In this manner, TNF might be neuroprotective in pathological conditions.

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