This proposal will examine the mechanism involved in the activation of CCAAT enhancer binding protein beta, C/EBPb, and its potential pro-apoptotic activity in the central nervous system (CNS). C/EBPb is a transcription factor expressed in many cell types, including neurons. Although substantial evidence suggests multiple roles for C/EBPb in non-neural cells, there is little information regarding its role or regulation in the CNS. However, our recent work demonstrates a connection between nuclear C/EBPb levels and survival of cerebellar granule neurons. In growth factor and L-type calcium channel-induced survival, nuclear levels are low, but in the absence of growth factor support or in NMDA receptor-mediated excitotoxic death, nuclear levels rise via rapid import from the cytoplasm; reducing nuclear levels with specific antisense oligonucleotides strongly promotes survival. Conversely, recent studies using hippocampal neurons have linked C/EBPb expression to the consolidation of long-term memory. Together, the data suggest that C/EBPb may play an important role(s) in the CNS, but leave unanswered both the generality of C/EBPb -dependent regulation and the specifics of the mechanism. Here, we will determine: 1) How are nuclear C/EBPb levels regulated? 2) The role of NMDA receptors in regulating C/EBPb translocation in hippocampal neurons, and 3) Is C/EBPb involved in hypo- and hyperglycemic-induced death of central neurons? Together, the proposed experiments will significantly advance our understanding of the mechanisms that regulate neuronal death and survival in the CNS.
