Transcriptional Responses in Recovery from Stroke
Multiple lines of evidence support synaptic reorganization of the brain after stroke and a role in functional recovery. Molecular, pharmacological, especially norardrenergic, and behavioral methods have shown promise in enhancing recovery in animal or clinical studies. However, the mechanisms underlying stimulation of new synapses remain largely unknown, information that is critical to optimize interventions, including stem cell transplant, drug therapy or other approaches. We investigated two potential such mechanisms in a rat model of middle cerebral artery occlusion (MCAO) in which we have previously shown robust new expression of the pre-synaptic vesicle protein synaptophysin in the peri-infarct and contralateral homotopic regions. One candidate signal for stimulation of new synaptic formation is the polysialated form of neuronal cell adhesion molecules (PSCAM) that is expressed during synaptic development. Immunostaining for PSCAM after MCAO and recovery failed to demonstrate expression. The possibility that signal molecules potentially released following ischemia, may be involved in synaptic generation analogous to long term potentiation (LTP), was next investigated. The C/EBP (CCAAT enhancer binding protein) family of transcription factors is an important intermediary for glutamate stimulation of synapses in LTP. After distal MCAO in rats, we found dramatic expression of the C/EBP α subtype in the peri-infarct region at 3 days, and expression by Western blot of a 30 kD C/EBP α isoform in cultured PC12 cells induced to differentiate into neurite and synapses. We suggest the possibility that C/EBP, stimulated by biochemical events in the peri-infarct region, is a potential signal for new synapses following stroke. We are in the process of assessing the effect of overexpression of this isoform on synapse formation in cultured PC12 cells. C/EBP α and other signals may provide targets for intervention to enhance expression. The importance of these results as related to the effects of glutamate also support our previous finding that glutamate-blockade, although limiting infarct size, may also interfere with synapse formation in the long term (Bolanos & Kent, JCBF & Met Suppl, 1999).