Occurrence and functional significance of serotonin and catecholamine uptake by astrocytes.

Serotonin (5HT), and the catecholamines norepinephrine (NE) and dopamine (DA), are important nervous system transmitters. Traditionally, these and other transmitters have been viewed as excitatory or inhibitory “switching” mechanisms at synapses in the nervous system. There is now a growing interest in the involvement of the catecholamines and serotonin in more “modulatory” effects on brain function [ 11, and also in the development of the nervous system [2]. An important factor in allowing these transmitters to effectively fulfil1 any of these roles is, of course, the ability to control both the initiation and termination of their action. In the mammalian nervous system, initiation of action is thought to be due to release of transmitters from presynaptic nerve endings by the exocytosis of vesicles in which these transmitters are stored. Termination of the action of transmitters, after they have combined with postsynaptic receptors and achieved their specific effects, is thought to be mainly by re-uptake mechanisms located in the same nerve terminals from which they were released. This scheme is now an established textbook tenet (e.g. Refs. 3-5) and is well-accepted in the literature, e.g. “both in the PNS and CNS, the high affinity membrane systems for catecholamines appear to be exclusively neuronal” and “there is strong evidence for the existence of a high-affinity transport of 5-HT into peripheral and central serotonergic neurons” [6]. However, many synapses in the CNS are surrounded by the processes of astroglial cells (astrocytes) [7-lo]. These cells, together with oligodendroglia, constitute the macroglia which represent the major portion of the non-neuronal cells in the CNS. This perisynaptic location of astrocytes has long led neuroscientists to seriously consider that these cells may have a role in transmitter uptake. Thus, Lugaro as early as 1907 [9] wrote “Elsewhere, I have presented the argument that the action that is carried out at the level of the neuronal articulation between the nervous termination and the dendrites and cellular bodies of successive neurons is of a chemical nature. Every nervous termination suffers a chemical modification and this chemical modification in turn gives stimulus to another neurone. If this is true, the intemeuronal articulation (i.e. synapse) would be the center of the chemical exchange, and this would comprise therefore in all the most proximal, vacant interstitial spaces, a region for infiltration of the protoplasmic prolongations or feathery extensions of the neuroglia, perhaps with the purpose of collecting and instantly processing the smallest amount of waste product.” If we interpret “waste product” as released transmitters, we come up with a pretty good description of glial uptake of released transmitters at the synapse. In this commentary I will review recent evidence indicating that there may indeed be significant uptake of catecholamines and serotonin into astrocytes, in addition to the already established evidence for neuronal re-uptake. I will also present possible reasons why such uptake has not been seen so far in situ, and speculate on the possible roles for astrocytic uptake based on the limited data available.