Structure-Based Models of NO Diffusion in the Nervous System - Computational Neuroscience: A Comprehensive Approach - page 96

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 [22] 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 two-dimensionally
(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 neurotransmis-
sion 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, per-
haps the majority, cannot be simply classified as excitatory or inhibitory [17]. 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 me-
diated by the chemicals released by neurons.
However, when coupled with this expanded picture of the nervous system, it is
the recent discovery that the gas nitric oxide is a modulatory neurotransmitter that
has opened entirely unexpected dimensions in our thinking about neuronal chemical
signaling [14, 15, 19]. Because NO is a very small and nonpolar molecule it dif-
fuses isotropically in aqueous and lipid environments, such as the brain, regardless
of intervening cellular structures [47]. NO therefore violates some of the key tenets
of point-to-point chemical transmission and is the first known member of an entirely
new class of transmitter, the gaseous diffusable modulators ( CO and H 2 S are the other
two identified examples (see e.g., [4]. NO is generated in the brain by specialised
neurons that contain the neuronal isoform of the calcium activated enzyme, nitric ox-
ide synthase or nNOS [3]. NO synthesis is triggered when the calcium concentration
in nNOS-containing neurons is elevated, either by electrical activity or by the action
of other modulatory neurotransmitters. NO activates the synthesis of cyclic-GMP,
an important second messenger which regulates a wide variety of cellular processes
in target neurons, some of which underlie synaptic plasticity [19]. Hence NO is in-
volved in many neuronal functions from visual processing to memory formation and
blood flow regulation [16, 19, 46].