Nitric oxide: linking space and time in the brain.

It has been a key tenet of modem brair science that the central nervous system (CNS) processes signals by electrical and chemical transmission. In general, such transmission occurs locally via synapses, neuron to neuron. Images of wires, relays, and unit-to-unit signal transfer are prompted by these observations. The idea that units of brain function might, in fact, be whole groups of cooperatively interactive neurons (1) and that spatial signals involving volumes ofneural tissue may be important (2) has drawn the attention of the neuroscience community only recently. One reason for this change in viewpoint is the suggestion that nitric oxide (NO), a diffusible free radical with a short lifetime, might play a key role as a spatial signal controlling cerebral blood flow, changes in synaptic efficacy, and transmitter release. NO has recently been found to mediate a large number of diverse physiologic functions in many organs (3). In the cardiovascular, genitourinary, gastrointestinal, and renal systems, it acts in a critical manner to relax smooth muscles. In the immune system, it can act to inhibit the cell proliferation that is necessary to mount effective immune responses; at other times, it serves as a toxic agent aimed at pathogens. A possible role ofNO in the vertebrate CNS was first suggested by a report of Garthwaite et al. (4) that cerebellar neurons synthesize NO in response to excitatory neurotransmitters. Bredt and Snyder (5) isolated and characterized the neuronal enzyme, NO synthase [now known to be equivalent to NADPH diaphorase (6)], and they investigated the distribution of this enzyme throughout the CNS. It had been known for some time that drugs such as the nitrovasodilators could prevent strokes (but could also cause headaches), as a result of their effects on cerebral circulation. All of these observations prompt one to wonder whether NO might play a fundamental role in the key aspect of brain function: the processing of neural signals. The possibility that NO is a neurotransmitter has been considered (5), but its chemical properties appear to make it quite unsuitable for such a role, at least as a transmitter is classically defined: a substance mediating a signal from one side of a single synaptic cleft to lanother. As a hydrophobic diatomic moliecule, NO freely diffuses down a concenI tration gradient across cell membranes land thus cannot be localized within any organelle or bounded tissue compartment. In terms of its diffusion constant and its biological half-life in the brain, NO is very similar to molecular oxygen. |Moreover, since NO is a free radical that ris rapidly oxidized in the internal envilronment, it has a half-life within the CNS on the order ofa few seconds, and for this reason also it cannot be stored for subsequent release. The short life and ready diffusibility of NO uniquely qualify it to serve in a novel role in the CNS, that ofa spatial signal. In the NO hypothesis, we have suggested three important functions in the CNS for which a spatial signal might be required and have advanced the view that NO is a suitable candidate (7). As a spatial signal, it would act (i) to couple local levels of neural activity in the brain to local blood flow, accounting, for example, for changes measured in positron-emission tomography scans; (ii) to guide changes of synaptic efficacy within a local volume in such a manner that synapses that are coactive within short time periods are strengthened or stabilized; and (iii) to direct the growth of axonal arbors during development such that terminals of axons with correlated temporal patterns of firing are segregated into common anatomical volumes. This third function, which might be critical in the formation of cortical maps, provides a possible mechanism for the experimental observation that, in the brain, axon terminals that "fire together, wire together. " The first two of these proposals have now received experimental support. I Northington et al. (8), for example, have i demonstrated that the introduction of an inhibitor of NO synthase uncouples the increased flow of blood into the somai tosensory cortex that normally accompaI nies stimulation of peripheral nerves. Similarly, a number of laboratories have demonstrated that inhibitors of NO syn1 thesis block long-term potentiation of I synaptic strengths induced in hippocama pal slices as well as the induction of c long-term depression of cerebellar synr apses (for review, see ref. 9). The potenc tial significance of these NO-dependent ( changes in synaptic strengths on overall il animal behavior has been suggested by a report that inhibitors of NO synthase partially block spatial learning in rats (10). That NO release might direct synaptogenesis during development has not yet been subjected to experimental test, but it has been found that a population of neurons containing NO synthase does play a necessary role in cortical map formation (11). Computer simulations have shown that a short-lived spatial signal could give rise to such maps (12). The sparse patchy reciprocal connectivity of the axonal arbors generated in these simulations resembles those found by neuroanatomists as a very general feature of the brain, one that tends to link neighboring cortical neurons with similar response properties into neuronal groups that are reentrantly interconnected with one another (1). More recently, evidence has been obtained (13-15) to support a fourth physiologic function of NO in the CNS: to facilitate the release ofneurotransmitters within local tissue volumes. It has been known for some time that N-methyl-Daspartate (NMDA), a chemical analog of glutamate, the major excitatory neurotransmitter in the brain, would induce the release of neurotransmitters from catecholaminergic nerve endings. This has been offered as evidence for the existence of presynaptic NMDA receptors. An alternative mechanism that might account for this release would be that postsynaptic NMDA receptors exist on neurons that contain NO synthase and that the NO produced from these cells subsequent to Ca2+ influx through NMDA receptor channels acts as a spatial signal to facilitate the release of neurotransmitters from surrounding synapses. This is supported by the finding (13) that nitroarginine, a NO synthase nhibitor, or hemoglobin, a NO scavenger, inhibits dopamine release from striatal slices. These experimental results suggest that NO might serve to link the two different sorts of synaptic activity present in the vertebrate cortex and striatum: (i) that which is topographically organized within the sensory and motor maps and dependent on thalamocortical or intrinsic cortical neuronal activity and (ii) that which is a consequence of activity in the diffuse ascending system arising