Glial cells are widely distributed throughout the nervous system, including at the chemical synapse. However, our knowledge of the role of glial cells at the synapse is rudimentary. Recent studies using a model synapse, the vertebrate neuromuscular junction (NMJ), have demonstrated that perisynaptic Schwann cells (PSCs), which are the glia juxtaposed to the nerve terminal at the NMJ, play active and essential roles in synaptic function, maintenance, and development. PSCs can respond to nerve activity by increasing intracellular calcium and are capable of modulating synaptic function in response to pharmacological manipulations. Studies using PSC ablation in vivo have shown that PSCs are essential for the long-term maintenance of synaptic structure and function at the adult NMJ. In vivo observations have also shown that PSCs guide presynaptic nerve terminal extension and dictate the pattern of innervation during synaptic regeneration and remodeling at adult NMJs. PSCs may also induce postsynaptic acetylcholine receptor aggregation. Furthermore, PSCs play an essential role in synaptic growth and maintenance during development of NMJs in vivo, and Schwann cell-derived factors can promote synaptogenesis and enhance synaptic transmission in tissue culture. These recent findings advance the emerging concept that glial cells help make bigger, stronger, and more stable synapses.
Araque A, Parpura V, Sanzgiri RP, Haydon PG. 1999. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci22:208-215.
2.
Astrow SH, Qiang H, Ko CP. 1998. Perisynaptic Schwann cells at neuromuscular junctions revealed by a novel monoclonal antibody. J Neurocytol27:667-681.
3.
Astrow SH, Tyner TR, Nguyen MT, Ko CP. 1997. A Schwann cell matrix component of neuromuscular junctions and peripheral nerves. J Neurocytol26:63-75.
4.
Auld DS, Colomar A, Belair EL, Castonguay A, Pinard A, Rousse I, and others. 2003. Modulation of neurotransmission by reciprocal synapse-glial interactions at the neuromuscular junction. J Neurocytol32:1003-1015.
5.
Auld DS, Robitaille R.2003a. Glial cells and neurotransmission: an inclusive view of synaptic function. Neuron40:389-400.
6.
Auld DS, Robitaille R.2003b. Perisynaptic Schwann cells at the neuromuscular junction: nerve- and activity-dependent contributions to synaptic efficacy, plasticity, and reinnervation. Neuroscientist9:144-157.
7.
Bishop DL, Misgeld T, Walsh MK, Gan WB, Lichtman JW. 2004. Axon branch removal at developing synapses by axosome shedding. Neuron44:651-661.
8.
Bourque MJ, Robitaille R.1998. Endogenous peptidergic modulation of perisynaptic Schwann cells at the frog neuromuscular junction. J Physiol512(Pt 1):197-209.
9.
Cao G, Ko CP. 2001. Schwann cell-conditioned medium modulates synaptic activities at Xenopus neuromuscular junction in vitro. Soc Neurosci Abstr2001. Program Number 711.12.
10.
Castonguay A, Robitaille R.2001. Differential regulation of transmitter release by presynaptic and glial Ca2+ internal stores at the neuromuscular synapse. J Neurosci21:1911-1922.
11.
Chen L, Ko CP. 1994. Extension of synaptic extracellular matrix during nerve terminal sprouting in living frog neuromuscular junctions. J Neurosci14:796-808.
12.
Chen LL, Folsom DB, Ko CP. 1991. The remodeling of synaptic extra-cellular matrix and its dynamic relationship with nerve terminals at living frog neuromuscular junctions. J Neurosci11:2920-2930.
13.
Chiu SY. 1991. Functions and distribution of voltage-gated sodium and potassium channels in mammalian Schwann cells. Glia4:541-558.
14.
Corfas G, Velardez MO, Ko CP, Ratner N, Peles E.2004. Mechanisms and roles of axon-Schwann cell interactions. J Neurosci24: 9250-9260.
15.
Day NC, Wood SJ, Ince PG, Volsen SG, Smith W, Slater CR, and others. 1997. Differential localization of voltage-dependent calcium channel alpha1 subunits at the human and rat neuromuscular junction. J Neurosci17:6226-6235.
16.
Dickens P, Hill P, Bennett MR. 2003. Schwann cell dynamics with respect to newly formed motor-nerve terminal branches on mature (Bufo marinus) muscle fibers. J Neurocytol32:381-392.
17.
English AW. 2003. Cytokines, growth factors and sprouting at the neuromuscular junction. J Neurocytol32:943-960.
18.
Feng ZH, Ko CP. 2004. Transforming growth factor (TGF)-beta1 mediates Schwann cell-induced synaptogenesis at the neuromuscular junction in vitro. Soc Neurosci Abstr2004. Session Number 385.18.
19.
Georgiou J, Charlton MP. 1999. Non-myelin-forming perisynaptic schwann cells express protein zero and myelin-associated glycoprotein. Glia27:101-109.
20.
Georgiou J, Robitaille R, Charlton MP. 1999. Muscarinic control of cytoskeleton in perisynaptic glia. J Neurosci19:3836-3846.
21.
Halstead SK, O’Hanlon GM, Humphreys PD, Morrison DB, Morgan BP, Todd AJ, and others. 2004. Anti-disialoside antibodies kill perisynaptic Schwann cells and damage motor nerve terminals via membrane attack complex in a murine model of neuropathy. Brain127:2109-2123.
22.
Herrera AA, Banner LR, Nagaya N.1990. Repeated, in vivo observation of frog neuromuscular junctions: remodelling involves concurrent growth and retraction. J Neurocytol19:85-99.
23.
Herrera AA, Qiang H, Ko CP. 2000. The role of perisynaptic Schwann cells in development of neuromuscular junctions in the frog (Xenopus laevis). J Neurobiol45:237-254.
24.
Jahromi BS, Robitaille R, Charlton MP. 1992. Transmitter release increases intracellular calcium in perisynaptic Schwann cells in situ. Neuron8:1069-1077.
25.
Jordan CL, Williams TJ. 2001. Testosterone regulates terminal Schwann cell number and junctional size during developmental synapse elimination. Dev Neurosci23:441-451.
26.
Kang H, Tian L, Thompson W.2003. Terminal Schwann cells guide the reinnervation of muscle after nerve injury. J Neurocytol32:975-985.
27.
Kelly AM, Zacks SI. 1969. The fine structure of motor endplate morphogenesis. J Cell Biol42:154-169.
Ko CP. 1987. A lectin, peanut agglutinin, as a probe for the extracellular matrix in living neuromuscular junctions. J Neurocytol16: 567-576.
30.
Ko CP, Chen L.1996. Synaptic remodeling revealed by repeated in vivo observations and electron microscopy of identified frog neuromuscular junctions. J Neurosci16:1780-1790.
31.
Koirala S, Ko CP. 2004. Pruning an axon piece by piece; a new mode of synapse elimination. Neuron44:578-580.
32.
Koirala S, Qiang H, Ko CP. 2000. Reciprocal interactions between perisynaptic Schwann cells and regenerating nerve terminals at the frog neuromuscular junction. J Neurobiol44:343-360.
33.
Koirala S, Reddy LV, Ko CP. 2003. Roles of glial cells in the formation, function, and maintenance of the neuromuscular junction. J Neurocytol32:987-1002.
34.
Lichtman JW, Magrassi L, Purves D.1987. Visualization of neuromuscular junctions over periods of several months in living mice. J Neurosci7:1215-1222.
35.
Lin W, Sanchez HB, Deerinck T, Morris JK, Ellisman M, Lee KF. 2000. Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice. Proc Natl Acad Sci U S A97:1299-1304.
36.
Love FM, Thompson WJ. 1998. Schwann cells proliferate at rat neuromuscular junctions during development and regeneration. J Neurosci18:9376-9385.
37.
Love FM, Thompson WJ. 1999. Glial cells promote muscle reinnervation by responding to activity-dependent postsynaptic signals. J Neurosci19:10390-10396.
38.
Lubischer JL, Bebinger DM. 1999. Regulation of terminal Schwann cell number at the adult neuromuscular junction. J Neurosci19:RC46.
39.
Macleod GT, Dickens PA, Bennett MR. 2001. Formation and function of synapses with respect to Schwann cells at the end of motor nerve terminal branches on mature amphibian (Bufo marinus) muscle. J Neurosci21:2380-2392.
40.
Marques G, Bao H, Haerry TE, Shimell MJ, Duchek P, Zhang B, and others. 2002. The Drosophila BMP type II receptor Wishful Thinking regulates neuromuscular synapse morphology and function. Neuron33:529-543.
41.
Mayer C, Quasthoff S, Grafe P.1998. Differences in the sensitivity to purinergic stimulation of myelinating and non-myelinating Schwann cells in peripheral human and rat nerve. Glia23:374-382.
42.
McCabe BD, Marques G, Haghighi AP, Fetter RD, Crotty ML, Haerry TE, and others. 2003. The BMP homolog Gbb provides a retrograde signal that regulates synaptic growth at the Drosophila neuromuscular junction. Neuron39:241-254.
43.
Morris JK, Lin W, Hauser C, Marchuk Y, Getman D, Lee KF. 1999. Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development. Neuron23:273-283.
44.
Newman EA, Volterra A.2004. Glial control of synaptic function. Glia47:207-208.
45.
Peng HB, Yang JF, Dai Z, Lee CW, Hung HW, Feng ZH, and others. 2003. Differential effects of neurotrophins and Schwann cell-derived signals on neuronal survival/growth and synaptogenesis. J Neurosci23:5050-5060.
46.
Reddy LV, Koirala S, Sugiura Y, Herrera AA, Ko CP. 2003. Glial cells maintain synaptic structure and function and promote development of the neuromuscular junction in vivo. Neuron40:563-580.
47.
Reist NE, Smith SJ. 1992. Neurally evoked calcium transients in terminal Schwann cells at the neuromuscular junction. Proc Natl Acad Sci U S A89:7625-7629.
48.
Reynolds ML, Woolf CJ. 1992. Terminal Schwann cells elaborate extensive processes following denervation of the motor endplate. J Neurocytol21:50-66.
49.
Rimer M, Prieto AL, Weber JL, Colasante C, Ponomareva O, Fromm L, and others. 2004. Neuregulin-2 is synthesized by motor neurons and terminal Schwann cells and activates acetylcholine receptor transcription in muscle cells expressing ErbB4. Mol Cell Neurosci26:271-281.
50.
Robitaille R.1995. Purinergic receptors and their activation by endogenous purines at perisynaptic glial cells of the frog neuromuscular junction. J Neurosci15:7121-7131.
51.
Robitaille R.1998. Modulation of synaptic efficacy and synaptic depression by glial cells at the frog neuromuscular junction. Neuron21:847-855.
52.
Robitaille R, Bourque MJ, Vandaele S.1996. Localization of L-type Ca2+ channels at perisynaptic glial cells of the frog neuromuscular junction. J Neurosci16:148-158.
53.
Robitaille R, Jahromi BS, Charlton MP. 1997. Muscarinic Ca2+ responses resistant to muscarinic antagonists at perisynaptic Schwann cells of the frog neuromuscular junction. J Physiol504 (Pt 2):337-347.
54.
Rochon D, Rousse I, Robitaille R.2001. Synapse-glia interactions at the mammalian neuromuscular junction. J Neurosci21:3819-3829.
55.
Sanes JR, Lichtman JW. 1999. Development of the vertebrate neuromuscular junction. Annu Rev Neurosci22:389-442.
56.
Slezak M, Pfrieger FW. 2003. New roles for astrocytes: regulation of CNS synaptogenesis. Trends Neurosci26:531-535.
57.
Son YJ, Thompson WJ. 1995a. Nerve sprouting in muscle is induced and guided by processes extended by Schwann cells. Neuron14:133-141.
58.
Son YJ, Thompson WJ. 1995b. Schwann cell processes guide regeneration of peripheral axons. Neuron14:125-132.
59.
Sontheimer H.1994. Voltage-dependent ion channels in glial cells. Glia11:156-172.
60.
Tam SL, Gordon T.2003. Neuromuscular activity impairs axonal sprouting in partially denervated muscles by inhibiting bridge formation of perisynaptic Schwann cells. J Neurobiol57:221-234.
61.
Thastrup O, Cullen PJ, Drobak BK, Hanley MR, Dawson AP. 1990. Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)ATPase. Proc Natl Acad Sci U S A87:2466-2470.
62.
Trachtenberg JT, Thompson WJ. 1997. Nerve terminal withdrawal from rat neuromuscular junctions induced by neuregulin and Schwann cells. J Neurosci17:6243-6255.
63.
Ullian EM, Christopherson KS, Barres BA. 2004. Role for glia in synaptogenesis. Glia47:209-216.
64.
Ullian EM, Harris BT, Wu A, Chan JR, Barres BA. 2004. Schwann cells and astrocytes induce synapse formation by spinal motor neurons in culture. Mol Cell Neurosci25:241-251.
65.
Verkhratsky A, Steinhauser C.2000. Ion channels in glial cells. Brain Res Brain Res Rev32:380-412.
66.
Woldeyesus MT, Britsch S, Riethmacher D, Xu L, Sonnenberg-Riethmacher E, Abou-Rebyeh F, and others. 1999. Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development. Genes Dev13:2538-2548.
67.
Wolpowitz D, Mason TB, Dietrich P, Mendelsohn M, Talmage DA, Role LW. 2000. Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron25:79-91.
68.
Woolf CJ, Reynolds ML, Chong MS, Emson P, Irwin N, Benowitz LI. 1992. Denervation of the motor endplate results in the rapid expression by terminal Schwann cells of the growth-associated protein GAP-43. J Neurosci12:3999-4010.
69.
Yang JF, Cao G, Koirala S, Reddy LV, Ko CP. 2001. Schwann cells express active agrin and enhance aggregation of acetylcholine receptors on muscle fibers. J Neurosci21:9572-9584.
