Two reports demonstrate the importance of signaling to the adenosine 3′-5′ monophosphate (cAMP) response-element-binding protein (CREB) for neuronal survival. Lonze et al. reported enhanced apoptosis and neuronal degeneration, as well as defects in axon growth in mouse embryos deficient for the Creb gene. Hardingham et al. discovered that in hippocampal neurons in culture two pathways can regulate CREB activity and that the extrasynaptic pathway that inhibits CREB activity can result in apoptosis. Analysis of the Creb −/− mice showed that by embryonic day 17.5 there was increased apoptosis and loss of peripheral neurons of the trigeminal ganglia, dorsal root ganglia (DRG), and superior cervical ganglia. At earlier times, neuron number and morphology of the DRG was similar to wild-type mouse DRG, which suggests that CREB is not required for the initial differentiation of sensory neurons, but is required for neuronal survival. Hardingham et al. monitored the phosphorylation of CREB and the expression of CRE-containing genes in response to activation of synaptic and extrasynaptic N-methyl-D-aspartate type of glutamate receptors. They found that activation of synaptic glutamate receptors (by evoked action potentials) stimulated CREB phosphorylation and CRE-dependent gene expression. However, activation of extrasynaptic receptors (by bath application of glutamate under conditions in which the synaptic receptors were inhibited) promoted CREB dephosphorylation and promoted apoptosis of the cells. Thus, the compartmentalized activation of glutamate receptor signaling can produce two opposing signals: one to activate CREB and to promote cell survival and one to inhibit CREB activity and to promote apoptosis. The implications of this dual signaling and the potential differences in these pathways during development are discussed by Riccio and Ginty.
B. E. Lonze, A. Riccio, S. Cohen, D. D. Ginty, Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB. Neuron 34, 371-385 (2002). [Online Journal]
G. E. Hardingham, Y. Fukunaga, H. Bading, Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neurosci. 5, 405-414 (2002). [Online Journal]
A. Riccio, D. D. Ginty, What a privilege to reside at the synapse: NMDA receptor signaling to CREB. Nature Neurosci. 5, 389-390 (2002). [Online Journal]