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Tripartite Synapses: Glia, the Unacknowledged Partner

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Tripartite Synapses: Glia, the Unacknowledged Partner L ETTERS TO THE EDITOR components of the stretch-reflex system that this ‘system’ also includes the major tulated to interconnect and integrate them include: (1) dorsal-root-ganglion cells with sensory and motor systems as well. In a for whatever behavior or function is under their peripheral process that ends in stri- widely used fear-conditioning paradigm, consideration. ated-muscle stretch receptors and their auditory stimuli are used as conditioning Larry Swanson central process that ends on ventral-horn stimuli, foot-shock (somatosensory) stim- Gorica Petrovich motoneurons; and (2) the innervated uli are used as unconditioned stimuli and Neuroscience Program, University of ventral-horn motoneurons themselves. In the behavior of the animal that follows the Southern California, Los Angeles, other words, the stretch-reflex system presentation of such stimuli relies on the CA 90089-2520, USA. itself consists of parts of two classical sys- somatomotor system. In fact, very wide- tems: the somatosensory (proprioceptive) spread parts of the nervous system must References and somatomotor systems. be active during fear conditioning and 1 Lanuza, E., Martínez-Marcos, A. and Martínez-García, F. (1999) Trends Lanuza and colleagues suggest that emotional learning in general. Neurosci. 22, 207 because the basolateral amygdala and cen- Unfortunately, there is no general, 2 Nieuwenhuys, R., ten Donkellar, H.J. tral amygdala are interconnected, and have systematic theory or taxonomy of the and Nicholson, C., eds (1997) The Central Nervous System of Vertebrates, been implicated in fear conditioning and organization of mammalian neural systems. Springer-Verlag emotional learning, these two brain areas The development of one could be a major 3 Swanson, L.W. and Petrovich, G.D. form part of a fear-conditioning and achievement of 21st-century neuroscience. (1998) Trends Neurosci. 21, 323–333 emotional-learning system. This is certainly Meanwhile, we have the classical sensory 4 Swanson, L.W., Lufkin, T. and 3 4 Colman, D.R. (1999) in Fundamental reasonable, as we indicated in our review . and motor systems , and an essentially infi- Neuroscience (Zigmond, M.J. et al., eds), However, it is important to acknowledge nite combination of circuits that are pos- pp. 9–37, Academic Press R EVIEW Tripartite synapses: glia, the unacknowledged partner Alfonso Araque, Vladimir Parpura, Rita P. Sanzgiri and Philip G. Haydon According to the classical view of the nervous system, the numerically superior glial cells have inferior roles in that they provide an ideal environment for neuronal-cell function. However, there is a wave of new information suggesting that glia are intimately involved in the active control of neuronal activity and synaptic neurotransmission. Recent evidence shows that glia respond to neuronal activity with an elevation of their internal Ca2+ concentration, which triggers the release of chemical transmitters from glia themselves and, in turn, causes feedback regulation of neuronal activity and synaptic strength. In view of these new insights, this article suggests that perisynaptic Schwann cells and synaptically associated astrocytes should be viewed as integral modulatory elements of tripartite synapses. Trends Neurosci. (1999) 22, 208–215 LIAL CELLS have a variety of roles in the nervous synapses: the perisynaptic Schwann cells at the neuro- Gsystem1. Some of these roles place the glial cells in muscular junction and the astrocytes of the CNS. a subservient position, which supports the physiology From this point onwards the word ‘glia’ will be used to of associated neurons. However, recent experimental refer to these two types of cell. Alfonso Araque, evidence suggests that some glial cells also interact In order to achieve the aims of this article it is unfor- Vladimir Parpura, closely with neurons and participate in the regulation tunately necessary to omit extensive discussions of par- Rita P. Sanzgiri of synaptic neurotransmission. This article aims to dis- ticular aspects of glial physiology. However, recent and Philip G. cuss the emerging evidence that indicates such a role reviews concerning astrocytes are available that focus Haydon are at the for glial cells and to propose that synapses are tripar- on Ca2+ homeostasis and signaling2–6, receptor distribu- Laboratory of tite, consisting of synaptically associated glia as well as tion2–6, metabolic support for neurons7,8, the clearance Cellular Signaling, the presynaptic and postsynaptic nerve terminals. of extracellular ions9 and neurotransmitters10,11, and Dept of Zoology In vertebrates, glia can be divided into four major the role of astrocytes in synaptogenesis12,13. and Genetics, Iowa categories. In the PNS are the Schwann cells, and in the The original demonstration of transmitter-induced State University, CNS are microglia, oligodendrocytes and astrocytes. elevations of intracellular Ca2+ concentration in glia, Ames, IA 50011, For the purposes of this article the discussion will be which can be either long-duration Ca2+ spikes or oscil- USA. limited to glial cells that are intimately associated with lations in Ca2+ levels14,15, aroused the interest of several 208 TINS Vol. 22, No. 5, 1999 0166-2236/99/$ – see front matter © 1999 Elsevier Science. All rights reserved. PII: S0166-2236(98)01349-6 A. Araque et al. – Tripartite synapses R EVIEW TABLE 1. Glia-induced neuronal modulation Stimulus to glial cell Assay Cellular system Consequences Pharmacological Refs sensitivity Electrical Calcium imaging Cell-cultured forebrain Increased neuronal Ca2+ levels Octanol 33 (rat) (gap-junction mediated) Mechanical Calcium imaging Cell-cultured visual cortex Increased neuronal Ca2+ levels AP5 23 Photostimulation (rat) (NMDA-receptor mediated) Bradykinin Mechanical Calcium imaging Cell-cultured cortex (rat) Increased neuronal Ca2+ levels not determined 34 Mechanical Calcium imaging Cell-cultured cortex and Increased neuronal Ca2+ levels CNQX and AP5 32 Electrical and electro- hippocampus (rat) and neuronal depolarization physiology (iGluR mediated) ACPD Calcium imaging Hippocampal slice (rat) Increased neuronal Ca2+ levels AP5 and NBQX 25 (iGluR mediated) 2+ Prostaglandin E2 Calcium imaging Hippocampal slice (rat) Increased neuronal Ca levels AP5 and NBQX 24 (iGluR mediated) Mechanical Electrophysiology Cell-cultured hippocampus Presynaptic inhibition of elicited MCPG and MAP4 35 (rat) excitatory and inhibitory synaptic transmission (mGluR mediated) Electrical Electrophysiology Cell-cultured hippocampus Increased frequency of spontaneous AP5 36 Mechanical (rat) miniature synaptic currents UV photolysis (NMDA-receptor mediated) Electrical Electrophysiology Cell-cultured hippocampus Neuronal slow-inward current CNQX and AP5 26,35,36 Mechanical (rat) and depolarization (iGluR UV photolysis mediated) Mechanical Electrophysiology Retina (rat) Modulation of light-induced NBQX, AP7, bicuculline 37 neuronal activity (iGluR and strychnine mediated) Guanine nucleotides Electrophysiology Neuromuscular junction Presynaptic inhibition of not determined 38 (frog) neuromuscular transmission Intracellular Electrophysiology Hippocampal slice (rat) Facilitation of miniature inhibitory CNQX and AP5 39 depolarization of synaptic currents (iGluR mediated) astrocytes Abbreviations: ACPD, 1-aminocyclopentane-2S,3R-dicarboxylate; AP5, D-2-amino-5-phosphonopentanoic acid; AP7, D-2-amino-7-phosphonoheptanoic acid; CNQX, 6-cyano-7- nitroquinoxaline-2,3-dione; iGluR, ionotropic glutamate receptor; MAP4, 2-amino-2-methyl-4-phosphonobutanoic acid; MCPG, a-methyl-4-carboxyphenylglycine; mGluR, metabotropic glutamate receptor; NBQX, 6-nitro-7-sulphamoylbenzo(f )quinoxaline-2,3-dione. neurobiologists. As discussed elsewhere, astrocytes pos- The mechanism of Ca2+-dependent glutamate release sess a large array of neurotransmitter receptors2–4. Many is not fully defined. However, it is unlikely to be medi- of these are coupled to second-messenger systems that ated by glutamate-transporter reversal because transport 2+ 2–4,14 2+ 23,24,26 cause the release of Ca from IP3-sensitive stores . inhibitors do not affect Ca -dependent release . The propensity of ligands that cause Ca2+ elevations The ability of a-latrotoxin27 and tetanus toxin24, respec- raises the question of their role in astrocyte function. tively, to stimulate and inhibit the release of endo- genous glutamate from astrocytes, points to an exo- Astrocytes release neurotransmitters cytotic pathway underlying Ca2+-dependent glutamate It has been known for more than two decades that release. However, a more thorough evaluation and care- glial cells can release chemical transmitters16–22. An ful ultrastructural studies are required before such a important question is whether transmitter substances mechanism can be attributed to this release pathway. can be released in response to elevations in Ca2+ con- Astrocytes isolated from the hippocampus and centration. Indeed, Ca2+-dependent glutamate release visual cortex23,24, as well as Schwann cells derived from has been demonstrated in cultured astrocytes23,24 and dorsal-root ganglia28, all show Ca2+-dependent gluta- in acutely isolated hippocampal slices24,25. Bradykinin, mate release, which suggests that it might be a wide- or co-activation of glutamate receptors by AMPA and spread property of glia. Whether other neurotransmit- 2+ 1-aminocyclopentane-1S,3R-dicarboxylate (ACPD), ters are subject to Ca -regulated release in astrocytes, is causes an elevation of Ca2+ levels in astrocytes, which unknown. For example,
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