Neuron Glia Signaling 4 Pathways

Interactions between neurons and glial cells occur throughout the nervous system during development, in synapse formation, and in many other functions under both normal and pathological conditions (Barres, 1991; Murphy et al., 1993; Nedergaard, 1994; Pfrieger and Barres, 1996; McCall et al., 1996; Pfrieger and Barres, 1997). Although there is no histological or physiological evidence of gap junctional pathways for direct communication between neurons and glial cells, there is a surprising array of intercellular interactions mediated by ions, metabolites, and various signaling molecules. This chapter describes some of the neuron-glia interactions mediated by neurotransmitters, calcium, and nitric oxide.

In addition to their conventional roles at nerve and muscle synapses, neurotransmitters provide a chemical pathway linking the activities of neurons and glial cells. In the vertebrate retina and throughout the CNS, neuro-transmitter amino acids constitute one of the principal classes of molecule mediating intercellular communication. Because precise regulation of the magnitude and duration of transmitter activity is required, there is a need to inactivate or remove the transmitter in an efficient and timely manner from synaptic sites. Unlike the mechanism whereby acetylcholine is inactivated, degradative enzymes for amino acids and other neuroactive compounds are not present extracellularly, and termination of transmitter action depends largely on reuptake into neurons and/or transport into glial cells (cf. Kanner, 1994). After uptake, the transmitter may be degraded, transported into synaptic vesicles for reuse (Kanner and Sharon, 1978; Kish et al., 1989), or converted to a precursor for subsequent transmitter synthesis (cf. Paulsen and Fonnum, 1990). The importance of membrane transporters for the viability and functional integrity of neural tissue cannot be overemphasized (cf. Müller et al., 1998); even cholinergic neurons re quire an active transport process to recapture choline following acetylcholine hydrolysis (Kuhar and Murrin, 1978).

Glial cells possess high-affinity, carrier-mediated transport systems, and it is now firmly established that glia are major players in the active removal of neuroactive substances (Henn and Hamberger, 1971; Henn et al., 1974; Erecinska, 1987; Hansson and Rönnbäck, 1991). Furthermore, their biochemical properties suggest that glial cells may be involved in transmitter degradation and recycling, and the electrophysiological properties of their transporters indicate that they are able to discharge neurotransmitter into the extracellular space (cf. Nicholls and Attwell, 1990; Martin, 1992). Indeed, the glutamate released from glial cells has been shown to provide a signaling pathway by which neuronal NMDA receptors can be activated (Parpura et al. 1994, 1995). The transport systems of Müller cells exhibit many of the same features as other forms of glia, and it is likely these cells are engaged in similar activities in the retina (cf. Linser et al., 1984; Sarthy, 1983; Brew and Attwell, 1987; Szatkowski etal., 1990).

Glial cell membranes also contain voltage-gated (Chapter 5) and ligand-gated channels that behave very much like their neuronal counterparts (MacVicar et al., 1989; Wyllie et al., 1991; Clark and Mobbs, 1992). Here, too, the Muller cell has proven a good model for study. The findings have provided new insights into the functional and pharmacological properties of glial receptors and amino acid transporters (Brew and Attwell, 1987; Nicholls andAttwell, 1990; Malchowetal., 1989; Qian etal., 1993,1996; Biedermann et al., 1995; Billups et al., 1996). Although the retina uses a multitude of neurotransmitters (cf. Adler, 1983; Pourcho et al., 1984; Biedermann et al., 1995), this chapter will focus primarily on neuron-glia interactions mediated by GABA and glutamate, the main inhibitory and excitatory amino acids, respectively, in retina and CNS. In addition, there is clear evidence that fluctuations in intracellular calcium, induced by activation of transmitter-gated ion channels, provide an important mechanism for neuron-glia signaling. Lastly, the observation that nitric oxide (NO) can serve as an intercellular messenger in neural tissues suggests yet another pathway for communication between neurons and glial cells (Garthwaite, 1991). Both cell types have the capacity to make NO, but whether glial cell NO affects neuronal function—and vice versa—is an issue that remains difficult to resolve. However, the emergence of NO as a major signaling molecule warrants consideration when discussing possible pathways for neuron-glia interactions.

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