Nonsynaptic communication in the central nervous system
Introduction
In the 19th century anatomists and physiologists, led by Santiago Ramón y Cajal, Wilhelm His and Charles Sherrington, developed the Neuron Theory, specifying a nervous system composed of discrete nerve cells communicating through their synaptic contacts. It was a significant progress from the idea of Golgi and Apáthy (1897) that the nervous system was composed of a reticulum of continuous, anastomosing fibers connecting everything with everything by means of protoplasmic processes. Golgi developed a silver staining technique to study fibrils. Apáthy (1897) and Bethe (1900) claimed that the “reticulum” was involved in continuity. They studied the leeches and found ,the slightest indication that the neurofilaments pass from one cell to another” (cf. Ramon y Cajal, 1937). For a very simple reason: the Golgi stain showed no indication of continuity. On the other hand, it did not show cell contacts either. Thomas Elliott, a student of Langley at Cambridge University obtained the first evidence of chemical transmission between nerve ending and target cell (Elliot, 1904). He proposed that that adrenaline was “the chemical stimulant liberated on each occasion when the [nerve] impulse arrives at the periphery” and responses to adrenaline were “of a similar character to that following excitation of the sympathetic … nerves” (Elliot, 1905). The idea of chemical neurotransmission was finally established by Loewi, Dale, Feldberg and others. Nevertheless our understanding of how the nervous system works was based to a large degree on exploiting the neuromuscular junction, spinal motorneuron, and sympathetic ganglia as models for the well-known end-plate potential (EPP), and excitatory and inhibitory postsynaptic potentials (EPSP and IPSP).
Synaptic transmission mediated by GABA, acetylcholine (ACh), glutamate, and glycine is characterized by ligand-gated ion channels with low affinity for the transmitters, which are released in the synapse in a concentration range of mM. The actions of these transmitters are typically restricted to the synaptic region and uptake is required for terminating the synaptic action of GABA, glutamate and glycine. In the case of acetylcholine, an enzyme (acetylcholine-esterase) is mainly responsible for the inactivation of the transmitter. There was a puzzle learning from electrophysiological studies that action potentials of the presynaptic partners can produce slow postsynaptic potentials (PSPs), with durations of seconds and minutes; features strikingly different from classical fast PSPs (Libet and Tosaka, 1969, Hartzell, 1981, Libet, 1992). A late sEPSP, with durations of up to several minutes, was first described in the frog sympathetic ganglion (Adams et al., 1986). In the mammalian sympathetic ganglion (rabbit SCG), a relatively large noncholinergic ssEPSP with durations of up to 30 min can be produced, even by a low-frequency train of preganglionic volleys (Mochida and Libet, 1988).
Section snippets
What morphology tells us about nonsynaptic communication forms
Existence of functional interactions between neurons without any morphological contact was first indicated by the findings that matches between release sites and localization of receptors sensitive to the chemical signal are exceptions rather than the rule (Herkenham, 1987). Although the disparities between axon terminals (release sites) and receptors were noted in several reports (cf. Herkenham, 1991). Even in the report on substance P receptors (Rothman et al., 1984), they put forth that
Functional evidence for nonsynaptic transmission
To establish the existence and the importance of nonsynaptic communication in the nervous system, in the followings we provide evidences for each step of the interneuronal communication in the nonsynaptic context. Release of transmitters from boutons without synaptic connections is one of the most important sources of information in the nonsynaptic system. In addition, transporters, which communicate with the extrasynaptic space by their nature, also contribute to the transmitter content of the
Nitric oxide (NO)
The first compound in this line was nitric oxide (NO), that was identified as an important regulator of vascular tone (Ignarro et al., 1987, Ikarashi et al., 1998). Later it has been shown that this compound participates also in the function of the central nervous system (Bredt and Snyder, 1994, Schuman and Madison, 1994). NO is produced from l-Arginine (l-Arg) by nitric oxide synthase (NOS). There are at least three different forms of this enzyme (Griffith and Stuehr, 1995), the endothelial
Nonconventional signal detection
As we described above, there is ample of evidence for the presence of conventional receptors in membranes located extrasynaptically. These receptors might detect signals mediated by conventional neurotransmitters that reach their targets by diffusion through the extrasynaptic space. However, the appearance of diffusible messengers has substantially broadened the spectrum of potential target sites. Although a common feature of these novel mediators, that they do not have classical receptors,
Concluding remarks
The previously presented data clearly show that many of the conventional transmitters and a number of nonconventional mediators are able to establish nonsynaptic connections between distant neuronal elements. A key question, however, whether this type of interaction has any physiological role in the function of the central nervous system. Accumulating evidence indicates that this cross-talk is not a marginal phenomenon but an important constituent of the higher brain functions. This is a tonic,
Acknowledgements
This study was supported by the Hungarian Research Fund (OTKA T 034622, T 32789 and Ts 040736), Phillip Morris USA Inc., and the Hungarian Medical Research Foundation (ETT 476/2003 and 068/2001).
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