Several observations suggest that the Ca2 -dependent postsynaptic release of nitric oxide (NO) may be important in the formation and function of the vertebrate nervous system. We explore here the hypothesis that the release of NO and its subsequent diffusion may be critically related to three aspects of nervous system function: (i) synaptic plasticity and long-term potentiation in certain regions of the adult nervous system, (i) the control of cerebral blood flow in such regions, and (iii) the establishment and activity-dependent refinement of axonal projections during the later stages of development. In this paper, we detail and analyze the basic assumptions underlying this NO hypothesis and describe a computer simulation of a minimal version of the hypothesis. In the simulation, a 3-dimensional volume of neuropil is presented with patterned afferent input; NO is produced, diffuses, and is destroyed; and synaptic strengths are determined by a set of synaptic rules based on the correlation of synaptic depolarization and NO levels. According to the hypothesis, voltagedependent postsynaptic release of this rapidly diffusing substance links the activities of neurons in a local volume of tissue, regardless of whether the neurons are directly connected by synapses. This property is demonstrated in the simulation, and it is this property that is exploited in the hypothesis to account for certain aspects of long-term potentiation and activitydependent sharpening of axonal arbors. Recent experiments indicate that nitric oxide (NO) is produced in the granule cells of the cerebellum in response to glutamate application (1, 2) . Other work demonstrates that NO is the endothelial-derived relaxing factor responsible for relaxation of vascular smooth muscle (3). The Ca2+-dependent enzyme nitric oxide synthetase is found in the vertebrate forebrain (4) as well as in the cerebellum (5). Cortical activity is well known to be accompanied by regionally specific changes in blood flow, and therefore we suggest that NO production in a cortical region is one cause of these local vascular responses. There are reasons to suggest an even more fundamental role for NO in altering synaptic efficacy within various brain regions in the adult as well as in synaptogenesis during development. For example, a body of data has accumulated demonstrating that the synaptic changes of long-term potentiation (LTP) result from the temporal correlation of presynaptic activity and postsynaptic depolarization (6). A number of studies support the notion that LTP is the result of separate presynaptic and postsynaptic components, both of which can contribute to its induction and maintenance (6-11). In development, the segregation and refinement of afferent projections also critically depends upon correlated electrical activity and synaptic changes both within afferent projections and between the afferents and their targets (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) . The Nmethyl-D-aspartate receptor and excitatory transmission in general have been implicated in this segregation (17, 18, 21, 22) . A relationship between LTP and activity-driven sharpening of axonal connections has been recently suggested (21, 22) . The question arises: what factors could subserve this relationship in neural regions extending beyond an interactive pair of neurons? An attractive possibility is that the developmental segregation of afferents and synaptic plasticity in the developed nervous system could both be subserved by diffusible paracrine factors that are released into the extracellular space. Arachidonic acid has been suggested as a candidate substance contributing to LTP (23, 24) . Recently, Williams et al. (23) have suggested that the signal from the postsynaptic site to the presynaptic site in LTP may be NO. In this paper, we propose that a signal with effects extending well beyond any such pair of synaptic elements is required to account for the observations. We emphasize those properties of NO that make it a particularly attractive candidate for such a signal. We suggest a hypothesis on the possible mode of synaptic action of NO in the adult and developing nervous system. We explore the proposed action of NO by explicit computer modeling of a minimal version of the hypothesis which is applicable to any diffusible substance with similar properties. BACKGROUND AND THEORY As illustrated in Fig. L4 , NO is rapidly released from cerebellar granule cells in response to the application ofglutamate or related amino acids (1, 2, 25, 26) . The glutamate effect is blocked by N-methyl-D-aspartate receptor antagonists (1, 25,
More specifically, there is some work on modelling the diffusion and signalling properties of NO in real neuronal networks REF Phillipides et al., 1998) .
The NO hypothesis: possible effects of a short-lived, rapidly diffusible signal in the development and function of the nervous system.
Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America
Biology Medicine