The role of extracellular ionic changes in upregulating the mRNA for glial fibrillary acidic protein following spreading depression.

While spreading depression has been shown to be a powerful stimulus in upregulating glial fibrillary acidic protein (GFAP) mRNA expression, the specific physiological signal underlying the upregulation is unknown. During spreading depression, extracellular ionic concentrations are altered markedly. The present study evaluates the role of these changes in extracellular ionic concentrations as potential signals influencing GFAP mRNA expression. Gel foam pledgets saturated with artificial cerebrospinal fluid (CSF) solutions in which [Na+], [Ca2+], [K+] and [H+] were altered one at a time to match concentrations seen in spreading depression were applied to exposed parietal cortex for one hour. Dot and in situ hybridization techniques were used to evaluate GFAP mRNA levels. We found that CSF containing 60 mM KCl produced a dramatic upregulation of GFAP mRNA levels throughout the cerebral cortex of the ipsilateral hemisphere without causing detectable tissue damage. The pattern and time course of the change were similar to those following application of 3 M KCl. Alteration of other ionic species did not affect GFAP mRNA levels. However, the upregulation of GFAP mRNA was not likely due directly to the increased [K+], but rather to the spreading depression that the elevated [K+] induced. This was demonstrated by the finding that the upregulation in GFAP mRNA induced by the potassium exposure was totally blocked by prior administration of MK-801, an NMDA antagonist that blocks spreading depression. These results demonstrate that an upregulation in GFAP mRNA can occur in the absence of degeneration debris and that the initiating events can be related to physiological changes, but that changes in extracellular ionic concentrations are not the likely molecular signals underlying the upregulation.