Induction of EGR1/NGFI-A Gene Expression by Spreading Depression and Focal Cerebral Ischemia

In situ hybridization was used to evaluate EGR 1 (NGFI-A) gene expression in the rat brain following focal ischemia caused by middle cerebral artery occlusion (MCAO). At 1 h postlesion (PL), there was a striking increase in EGR1 mRNA in neurons throughout the ipsilateral cortex, with a lesser increase occurring in a patchy distribution in the contralateral cortex. The ipsilateral hemispheric reaction was maximal at 1 h PL, slightly reduced after 3 and 5 h, and resolved after 24 h. Sham surgery limited to meningeal disruption resulted in a similar though less intense induction of EGR1 gene expression in the ipsilateral cortex only. After MCAO but not sham surgery, there was a vivid induction of EGR1 mRNA in the ipsilateral hippocampal formation (CA3 > CA1 > DG). While the hemispheric cortical and hippocampal increases in EGR1 expression had normalized at 24 h PL, intense EGR1 gene expression was seen in neurons of the infarct rim for several days. EGR1 mRNA was also increased in reactive glial cells in the infarct zone from 1 to 9 days after the infarct. In summary, successive waves of transient EGR1 gene expression mark the brain's response to ischemic injury: these include the widespread, unilateral cortical induction associated with the phenomenon of spreading depression, an apparent trans-synaptic activation of contralateral cortex and ipsilateral hippocampal formation-and more sustained responses in injured but surviving neurons and reactive glial cells. The extensive EGR1 expression demonstrated in this experimental paradigm suggests that EGR1 is a fundamental component of neural cell activation.