Structure based models of NO diffusion in the nervous system

While the transmission of electrical signals across neuronal networks is a fundamental aspect of the operation of nervous systems, and this feature has traditionally been the main focus of computational neuroscience (Koch and Segev 1998,Dayan and Abbott 2001), neurochemistry adds many dimensions to the picture. For instance, it is now recognised that nitric oxide (NO) is a novel kind of neurotransmitter that acts, through diffusion, over volumes that potentially contain many neurons and can facilitate signalling between neurons that are not synaptically connected (Gally et al. 1990,Wood and Garthwaite 1994,Vincent 1994). This article aims to demonstrate that computational and mathematical modelling have an important role to play in trying to understand this particularly interesting mode of signalling. Traditionally, chemical signaling between nerve cells was thought to be mediated solely by messenger molecules or neurotransmitters which are released by neurons at synapses (Katz 1969). and flow from the presynaptic to postsynaptic neuron. Because most neurotransmitters are relatively large and polar molecules (amino acids, amines and peptides), they cannot diffuse through cell membranes and do not spread far from the release site. They are also rapidly inactivated by various reactions. Together these features confine the spread of such neurotransmitters to be very close to the points of release and ensure that the transmitter action is transient. In other words, chemical synaptic transmission of the classical kind operates essentially twodimensionally (one in space and one in time). This conventional interpretation is coupled to the idea that neurotransmitters cause either an increase or a decrease in the electrical excitability of the target neuron. According to a traditional view of neurotransmission therefore, chemical information transfer is limited to the points of connection between neurons and neurotransmitters can simply be regarded as either excitatory or inhibitory. In recent years a number of important discoveries have necessitated a fundamental revision of this model. It is now clear that many neurotransmitters, perhaps the majority, cannot be simply classified as excitatory or inhibitory (Hall 1992). These messenger molecules are best regarded as modulatory because among other things they regulate, or modulate, the actions of conventional transmitters. Modulatory neurotransmitters act in an indirect way by causing medium and long-term changes in the properties of neurons by influencing the rate of synthesis of so called second messenger molecules. By altering the properties of proteins and even by changing the pattern of gene expression, these second messengers cause complex cascades of events resulting in fundamental changes in the properties of neurons. In this way modulatory transmitters greatly expand the diversity and the duration of actions mediated by the chemicals released by neurons.