Synaptic versus extrasynaptic NMDA receptor signaling: CREB makes the difference

Abstract

The NMDA receptor plays a key role during neuronal development and the induction of various forms of synaptic plasticity in the CNS, including long-term potentiation and long-term depression. However, prolonged activation of the same receptor under pathological conditions such as cerebral ischemia and traumatic injury causes neuronal cell death. What is the stimulus that triggers such a different cellular consequence? The NMDA receptor is highly permeable to Ca2? ions and it has been suggested that different sites and kinetics of Ca2? entry have an important role in triggering the two processes. Previous work demonstrated that Ca2? entry through L-type Ca2? channels promotes cell survival via the expression of CREB (cAMP response element-binding protein)-activated genes such as the gene encoding BDNF (brain-derived neurotrophic factor). By contrast, the exogenous application of glutamate inhibits CREB-dependent gene transcription and is neurotoxic to cells.