Roles of NMDA receptor activity and nitric oxide production in brain development

The concept that neural activity is important for brain maturation has focused much research interest on the developmental role of the NMDA receptor, a key mediator of experience-dependent synaptic plasticity. However, a mechanism able to link spatial and temporal parameters of synaptic activity during development emerged as a necessary condition to explain how axons segregate into a common brain region and make specific synapses on neuronal sub-populations. To comply with this developmental constraint, it was proposed that nitric oxide (NO), or other substances having similar chemical and biological characteristics, could act as short-lived, activity-dependent spatial signals, able to stabilize active synapses by diffusing through a local volume of tissue. The present article addresses this issue, by reviewing the experimental evidence for a correlated role of the activity of the NMDA receptor and the production of NO in key steps of neural development. Evidence for such a functional coupling emerges not only concerning synaptogenesis and formation of neural maps, for which it was originally proposed, but also for some earlier phases of neurogenesis, such as neural cell proliferation and migration. Regarding synaptogenesis and neural map formation in some cases, there is so far no conclusive experimental evidence for a coupled functional role of NMDA receptor activation and NO production. Some technical problems related to the use of inhibitors of NO formation and of gene knockout animals are discussed. It is also suggested that other substances, known to act as spatial signals in adult synaptic plasticity, could have a role in developmental plasticity. Concerning the crucial developmental phase of neuronal survival or elimination through programmed cell death, the well-documented survival role related to NMDA receptor activation also starts to find evidence for a concomitant requirement of downstream NO production. On the basis of the reviewed literature, some of the major controversial issues are addressed and, in some cases, suggestions for possible future experiments are proposed.