Modulation of gene activity may play a role in the transmission of cellular information during periods of neuronal plasticity. Activation of genes, such as c-fos, can occur in response to ion flux, peripheral nerve trauma, seizures, and growth factor release. In addition, the NMDA receptor has been linked to the regulation of c-fos expression. Blockade of the NMDA receptor has been shown to prevent the expression of c-fos proteins in rat cortex following focal cortical lesions. It has been proposed that the c-fos gene product, Fos, may function as a "third messenger" to link brief second messenger responses to prolonged adaptive changes that require modifications in gene expression. Expression of c-fos also is known to occur in conjunction with expression of the proto-oncogene c-jun. Together with c-fos protein, the c-jun protein can form a heterodimer and regulate the transcription of genes. Both c-fos and c-jun are known to be induced within minutes following transient global ischemia in the hippocampus and following focal cerebral ischemia. In addition, the release of glutamate can induce the expression of the immediate early genes egr-1, c-fos, and c-jun that can be blocked by NMDA receptor antagonism or PKC activity. Although the role of c-fos, c-jun, and egr-1 in neuronal injury is unknown, it is possible that activation of these immediate early response genes may regulate neuronal survival. We are actively investigating the role of gene induction during neuronal injury.
