The Schwann Song of the Glia-less Synapse
Authors: Erik M. Ullian, Ben A. Barres
Journal: Neuron (1998)

Although synapses throughout the brain are ensheathed by glial cells, the possibility that glia play an active role in synaptic function has received remarkably little attention. Glia passively help to maintain synaptic function by buffering ion concentrations, clearing released neurotransmitters, and providing metabolic substrates to synapses. But glia can also sense nearby neuronal activity. They depolarize in response to neuronal activity (7Orkand R.K. Nicholls J.G. Kuffler S.W. J. Neurophysiol. 1966; 29: 788-806Crossref PubMed Scopus (836) Google Scholar, 6Kelly J.P. Van Essen D.C. J. Physiol. 1974; 238: 515-547PubMed Google Scholar), and in hippocampal slices glia not only depolarize (1Bergles D.E. Jahr C.E. Neuron. 1997; 19: 1297-1308Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar; Lüsher et al., 1998) but also elevate their intracellular calcium levels in response to synaptic activity (2Dani J.W. Chernjavsky A. Smith S.J. Neuron. 1992; 8: 429-440Abstract Full Text PDF PubMed Scopus (638) Google Scholar). These studies show that glia are listening attentively to nearby synaptic conversations. But do glia talk back to the neurons? An indication that they might comes from recent culture experiments. When purified CNS neurons were cultured in serum-free medium together with trophic peptides that promoted their survival and growth, they formed ultrastructurally normal synapses upon each other but displayed little synaptic activity (8Pfrieger F.W. Barres B.A. Science. 1997; 227: 1684-1687Crossref Scopus (579) Google Scholar). Addition of purified astrocytes, which normally ensheath these synapses in vivo, increased spontaneous synaptic activity more than 70-fold and increased action potential–independent quantal release more than 10-fold. These studies showed that, at least in culture, developing neurons form inefficient synapses that require glial signals to become fully functional. Evidence that glia modulate synaptic transmission in the animal, however, has been more difficult to come by. In simple and elegant experiments9Robitaille R. Neuron. 1998; 21 (this issue,): 847-855Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar in this issue of Neuron has now provided convincing evidence that glia really do modulate synaptic transmission in a relatively intact tissue preparation. By taking advantage of a classical synaptic preparation, the frog neuromuscular junction, Robitaille was able to study the role of glia in synaptic function at a single synapse. Perisynaptic Schwann cells (PSCs) ensheath the neuromuscular junction (see figure) and, just as astrocytes do in the brain, sense and respond to high frequency nerve stimulation by increasing their intracellular calcium levels (5Jahromi B.S. Robitaille R. Charlton M.P. Neuron. 1992; 8: 1069-1077Abstract Full Text PDF PubMed Scopus (179) Google Scholar). Because previous studies have shown that such high frequency stimulation also progressively diminishes the evoked synaptic response, Robitaille wondered whether the Schwann cells might actively mediate this form of synaptic depression. To test this possibility, Robitaille pharmacologically manipulated the G proteins in the PSCs that mediate the Schwann cell calcium response to synaptic activity. He simultaneously recorded the nerve-evoked responses from the postsynaptic muscle fiber in the intact nerve–muscle preparation. Remarkably, activation of PSC G proteins with GTPγS reduced the evoked muscle response by nearly 60%, a reduction almost identical to the synaptic depression induced by high frequency stimulation. The decreased muscle response appeared to be largely presynaptic. It was neither associated with a change in amplitude and kinetics of miniature events nor affected by postsynaptic manipulations. Rather, the decreased muscle response resulted from a large decrease in quantal content, the average number of vesicles released in an evoked response. Consistent with these results, previous studies have suggested that synaptic depression at the neuromuscular junction results from a depletion of synaptic vesicles in the presynaptic nerve terminal, leaving fewer vesicles available for subsequent release (3Del Castillo J. Katz B. J. Physiol. 1954; 124: 574-585PubMed Google Scholar, 11Zucker R.S. Annu. Rev. Neurosci. 1989; 12: 13-31Crossref PubMed Scopus (1253) Google Scholar). These data were consistent with the possibility that Schwann cells mediate synaptic depression. To test this possibility directly, Robitaille examined the effects of inhibition of PSC G proteins by injecting GDPβS into the PSCs. This led to a 50% diminution of synaptic depression induced by high frequency stimulation. Moreover, when synapses were first depressed by injecting GTPγS, high frequency stimulation could induce little further depression, as expected if the two effects were mediated by the same mechanism. Taken together, Robitaille's findings demonstrate that Schwann cells play a crucial role in either modulating or mediating synaptic depression in response to high frequency stimulation at the neuromuscular junction, showing for the first time that Schwann cells actively participate in synaptic function. So how could Schwann cells reduce the number of synaptic vesicles released? An intriguing possibility is suggested by the work of 4Heuser J.E. Reese T.S. J. Cell Biol. 1973; 57: 315-344Crossref PubMed Scopus (1566) Google Scholar, who observed that at the frog neuromuscular junction, retrieval of fused synaptic vesicles occurs at sites just adjacent to contacting Schwann cells (see figure). Could stimulated Schwann cells signal the underlying terminal to slow the endocytotic recovery of synaptic vesicles, thereby regulating the size of the releasable vesicle pool? Such a model would fit in nicely with the slow endocytotic recovery rate of synaptic vesicles induced by high frequency stimulation at the frog neuromuscular junction (10Wu L.-G. Betz W.J. Neuron. 1996; 17: 769-779Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Whatever the mechanism, the Robitaille paper makes it clear that glia are not just listening to synaptic transmission but participating in the conversation as well.