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. 2001 Oct;81(4):1947–1959. doi: 10.1016/S0006-3495(01)75846-8

The role of perisynaptic glial sheaths in glutamate spillover and extracellular Ca(2+) depletion.

D A Rusakov 1
PMCID: PMC1301670  PMID: 11566769

Abstract

Recent findings suggest that rapid activation of extrasynaptic receptors and transient depletion of extracellular Ca(2+) may represent an important component of glutamatergic synaptic transmission. These phenomena imply a previously unrecognized role for synaptic glial sheaths: to retard extracellular diffusion in the synaptic vicinity. The present study is an attempt to assess the extent and physiological implications of this retardation using a detailed compartmental model of the typical synaptic environment. The model allows reconstruction of a partial (asymmetric) glial sheath covered with transporter molecules, which gives a more realistic representation of the vicinity of central synapses. Simulations show to what extent, in conditions compatible with physiology, the occupancy of synaptic receptors and the depletion of Ca(2+) in the cleft increase with increased glial coverage. The impact of glial sheaths on synaptic transmission is shown to become greater with smaller synapses and with slower kinetics of perisynaptic ion transients. At a calyceal synapse, a profound temporal filtering of fast Ca(2+) influx is found, and similar phenomena are predicted to occur following simultaneous activation of multiple synapses in the neuropil. The results provide a quantitative guidance for interpretation of physiological experiments that address fast transients of neurotransmitters and small ions in the brain tissue.

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Selected References

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  1. Araque A., Parpura V., Sanzgiri R. P., Haydon P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 1999 May;22(5):208–215. doi: 10.1016/s0166-2236(98)01349-6. [DOI] [PubMed] [Google Scholar]
  2. Arriza J. L., Fairman W. A., Wadiche J. I., Murdoch G. H., Kavanaugh M. P., Amara S. G. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci. 1994 Sep;14(9):5559–5569. doi: 10.1523/JNEUROSCI.14-09-05559.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Asztely F., Erdemli G., Kullmann D. M. Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake. Neuron. 1997 Feb;18(2):281–293. doi: 10.1016/s0896-6273(00)80268-8. [DOI] [PubMed] [Google Scholar]
  4. Auger C., Attwell D. Fast removal of synaptic glutamate by postsynaptic transporters. Neuron. 2000 Nov;28(2):547–558. doi: 10.1016/s0896-6273(00)00132-x. [DOI] [PubMed] [Google Scholar]
  5. Barbour B., Keller B. U., Llano I., Marty A. Prolonged presence of glutamate during excitatory synaptic transmission to cerebellar Purkinje cells. Neuron. 1994 Jun;12(6):1331–1343. doi: 10.1016/0896-6273(94)90448-0. [DOI] [PubMed] [Google Scholar]
  6. Bartol T. M., Jr, Land B. R., Salpeter E. E., Salpeter M. M. Monte Carlo simulation of miniature endplate current generation in the vertebrate neuromuscular junction. Biophys J. 1991 Jun;59(6):1290–1307. doi: 10.1016/S0006-3495(91)82344-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bergles D. E., Jahr C. E. Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. J Neurosci. 1998 Oct 1;18(19):7709–7716. doi: 10.1523/JNEUROSCI.18-19-07709.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Borst J. G., Sakmann B. Depletion of calcium in the synaptic cleft of a calyx-type synapse in the rat brainstem. J Physiol. 1999 Nov 15;521(Pt 1):123–133. doi: 10.1111/j.1469-7793.1999.00123.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brown E. M., Vassilev P. M., Hebert S. C. Calcium ions as extracellular messengers. Cell. 1995 Dec 1;83(5):679–682. doi: 10.1016/0092-8674(95)90180-9. [DOI] [PubMed] [Google Scholar]
  10. Bruns D., Jahn R. Real-time measurement of transmitter release from single synaptic vesicles. Nature. 1995 Sep 7;377(6544):62–65. doi: 10.1038/377062a0. [DOI] [PubMed] [Google Scholar]
  11. Carter A. G., Regehr W. G. Prolonged synaptic currents and glutamate spillover at the parallel fiber to stellate cell synapse. J Neurosci. 2000 Jun 15;20(12):4423–4434. doi: 10.1523/JNEUROSCI.20-12-04423.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Castejón O. J., Apkarian R. P., Valero C. Conventional and high resolution scanning electron microscopy and cryofracture techniques as tools for tracing cerebellar short intracortical circuits. Scanning Microsc. 1994;8(2):315–324. [PubMed] [Google Scholar]
  13. Castejón O. J. Freeze-fracture scanning electron microscopy and comparative freeze-etching study of parallel fiber-Purkinje spine synapses of vertebrate cerebellar cortex. J Submicrosc Cytol Pathol. 1990 Apr;22(2):281–295. [PubMed] [Google Scholar]
  14. Clements J. D. Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends Neurosci. 1996 May;19(5):163–171. doi: 10.1016/s0166-2236(96)10024-2. [DOI] [PubMed] [Google Scholar]
  15. Diamond J. S., Jahr C. E. Transporters buffer synaptically released glutamate on a submillisecond time scale. J Neurosci. 1997 Jun 15;17(12):4672–4687. doi: 10.1523/JNEUROSCI.17-12-04672.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Egelman D. M., Montague P. R. Calcium dynamics in the extracellular space of mammalian neural tissue. Biophys J. 1999 Apr;76(4):1856–1867. doi: 10.1016/s0006-3495(99)77345-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Egelman D. M., Montague P. R. Computational properties of peri-dendritic calcium fluctuations. J Neurosci. 1998 Nov 1;18(21):8580–8589. doi: 10.1523/JNEUROSCI.18-21-08580.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Haydon P. G., Henderson E., Stanley E. F. Localization of individual calcium channels at the release face of a presynaptic nerve terminal. Neuron. 1994 Dec;13(6):1275–1280. doi: 10.1016/0896-6273(94)90414-6. [DOI] [PubMed] [Google Scholar]
  19. Helmchen F., Borst J. G., Sakmann B. Calcium dynamics associated with a single action potential in a CNS presynaptic terminal. Biophys J. 1997 Mar;72(3):1458–1471. doi: 10.1016/S0006-3495(97)78792-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Isaacson J. S. Glutamate spillover mediates excitatory transmission in the rat olfactory bulb. Neuron. 1999 Jun;23(2):377–384. doi: 10.1016/s0896-6273(00)80787-4. [DOI] [PubMed] [Google Scholar]
  21. Janigro D., Gasparini S., D'Ambrosio R., McKhann G., 2nd, DiFrancesco D. Reduction of K+ uptake in glia prevents long-term depression maintenance and causes epileptiform activity. J Neurosci. 1997 Apr 15;17(8):2813–2824. doi: 10.1523/JNEUROSCI.17-08-02813.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jonas P., Major G., Sakmann B. Quantal components of unitary EPSCs at the mossy fibre synapse on CA3 pyramidal cells of rat hippocampus. J Physiol. 1993 Dec;472:615–663. doi: 10.1113/jphysiol.1993.sp019965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. King R. D., Wiest M. C., Montague P. R., Eagleman D. M. Do extracellular Ca2+ signals carry information through neural tissue? Trends Neurosci. 2000 Jan;23(1):12–13. doi: 10.1016/s0166-2236(99)01516-7. [DOI] [PubMed] [Google Scholar]
  24. Kleinle J., Vogt K., Lüscher H. R., Müller L., Senn W., Wyler K., Streit J. Transmitter concentration profiles in the synaptic cleft: an analytical model of release and diffusion. Biophys J. 1996 Nov;71(5):2413–2426. doi: 10.1016/S0006-3495(96)79435-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kruk P. J., Korn H., Faber D. S. The effects of geometrical parameters on synaptic transmission: a Monte Carlo simulation study. Biophys J. 1997 Dec;73(6):2874–2890. doi: 10.1016/S0006-3495(97)78316-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kuffler S. W., Nicholls J. G., Orkand R. K. Physiological properties of glial cells in the central nervous system of amphibia. J Neurophysiol. 1966 Jul;29(4):768–787. doi: 10.1152/jn.1966.29.4.768. [DOI] [PubMed] [Google Scholar]
  27. Lehre K. P., Danbolt N. C. The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci. 1998 Nov 1;18(21):8751–8757. doi: 10.1523/JNEUROSCI.18-21-08751.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lehre K. P., Levy L. M., Ottersen O. P., Storm-Mathisen J., Danbolt N. C. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci. 1995 Mar;15(3 Pt 1):1835–1853. doi: 10.1523/JNEUROSCI.15-03-01835.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lester R. A., Jahr C. E. NMDA channel behavior depends on agonist affinity. J Neurosci. 1992 Feb;12(2):635–643. doi: 10.1523/JNEUROSCI.12-02-00635.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mainen Z. F., Malinow R., Svoboda K. Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated. Nature. 1999 May 13;399(6732):151–155. doi: 10.1038/20187. [DOI] [PubMed] [Google Scholar]
  31. Mennerick S., Shen W., Xu W., Benz A., Tanaka K., Shimamoto K., Isenberg K. E., Krause J. E., Zorumski C. F. Substrate turnover by transporters curtails synaptic glutamate transients. J Neurosci. 1999 Nov 1;19(21):9242–9251. doi: 10.1523/JNEUROSCI.19-21-09242.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mitchell S. J., Silver R. A. GABA spillover from single inhibitory axons suppresses low-frequency excitatory transmission at the cerebellar glomerulus. J Neurosci. 2000 Dec 1;20(23):8651–8658. doi: 10.1523/JNEUROSCI.20-23-08651.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Mitchell S. J., Silver R. A. Glutamate spillover suppresses inhibition by activating presynaptic mGluRs. Nature. 2000 Mar 30;404(6777):498–502. doi: 10.1038/35006649. [DOI] [PubMed] [Google Scholar]
  34. Mody I., Heinemann U. Laminar profiles of the changes in extracellular calcium concentration induced by repetitive stimulation and excitatory amino acids in the rat dentate gyrus. Neurosci Lett. 1986 Aug 29;69(2):137–142. doi: 10.1016/0304-3940(86)90592-6. [DOI] [PubMed] [Google Scholar]
  35. Montague P. R. The resource consumption principle: attention and memory in volumes of neural tissue. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3619–3623. doi: 10.1073/pnas.93.8.3619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nicholson C. Interaction between diffusion and Michaelis-Menten uptake of dopamine after iontophoresis in striatum. Biophys J. 1995 May;68(5):1699–1715. doi: 10.1016/S0006-3495(95)80348-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Nicholson C. Modulation of extracellular calcium and its functional implications. Fed Proc. 1980 Apr;39(5):1519–1523. [PubMed] [Google Scholar]
  38. Nicholson C., Rice M. E. Calcium diffusion in the brain cell microenvironment. Can J Physiol Pharmacol. 1987 May;65(5):1086–1091. doi: 10.1139/y87-170. [DOI] [PubMed] [Google Scholar]
  39. Nicholson C., ten Bruggencate G., Stöckle H., Steinberg R. Calcium and potassium changes in extracellular microenvironment of cat cerebellar cortex. J Neurophysiol. 1978 Jul;41(4):1026–1039. doi: 10.1152/jn.1978.41.4.1026. [DOI] [PubMed] [Google Scholar]
  40. Nusser Z., Lujan R., Laube G., Roberts J. D., Molnar E., Somogyi P. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron. 1998 Sep;21(3):545–559. doi: 10.1016/s0896-6273(00)80565-6. [DOI] [PubMed] [Google Scholar]
  41. Otis T. S., Jahr C. E. Anion currents and predicted glutamate flux through a neuronal glutamate transporter. J Neurosci. 1998 Sep 15;18(18):7099–7110. doi: 10.1523/JNEUROSCI.18-18-07099.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Otis T. S., Kavanaugh M. P. Isolation of current components and partial reaction cycles in the glial glutamate transporter EAAT2. J Neurosci. 2000 Apr 15;20(8):2749–2757. doi: 10.1523/JNEUROSCI.20-08-02749.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pumain R., Heinemann U. Stimulus- and amino acid-induced calcium and potassium changes in rat neocortex. J Neurophysiol. 1985 Jan;53(1):1–16. doi: 10.1152/jn.1985.53.1.1. [DOI] [PubMed] [Google Scholar]
  44. Racca C., Stephenson F. A., Streit P., Roberts J. D., Somogyi P. NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area. J Neurosci. 2000 Apr 1;20(7):2512–2522. doi: 10.1523/JNEUROSCI.20-07-02512.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Reichenbach A. Glial K+ permeability and CNS K+ clearance by diffusion and spatial buffering. Ann N Y Acad Sci. 1991;633:272–286. doi: 10.1111/j.1749-6632.1991.tb15620.x. [DOI] [PubMed] [Google Scholar]
  46. Rossi D. J., Hamann M. Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry. Neuron. 1998 Apr;20(4):783–795. doi: 10.1016/s0896-6273(00)81016-8. [DOI] [PubMed] [Google Scholar]
  47. Rusakov D. A., Davies H. A., Harrison E., Diana G., Richter-Levin G., Bliss T. V., Stewart M. G. Ultrastructural synaptic correlates of spatial learning in rat hippocampus. Neuroscience. 1997 Sep;80(1):69–77. doi: 10.1016/s0306-4522(97)00125-5. [DOI] [PubMed] [Google Scholar]
  48. Rusakov D. A., Harrison E., Stewart M. G. Synapses in hippocampus occupy only 1-2% of cell membranes and are spaced less than half-micron apart: a quantitative ultrastructural analysis with discussion of physiological implications. Neuropharmacology. 1998 Apr-May;37(4-5):513–521. doi: 10.1016/s0028-3908(98)00023-9. [DOI] [PubMed] [Google Scholar]
  49. Rusakov D. A., Kullmann D. M. Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation. J Neurosci. 1998 May 1;18(9):3158–3170. doi: 10.1523/JNEUROSCI.18-09-03158.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Rusakov D. A., Kullmann D. M. Geometric and viscous components of the tortuosity of the extracellular space in the brain. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8975–8980. doi: 10.1073/pnas.95.15.8975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Rusakov D. A., Kullmann D. M., Stewart M. G. Hippocampal synapses: do they talk to their neighbours? Trends Neurosci. 1999 Sep;22(9):382–388. doi: 10.1016/s0166-2236(99)01425-3. [DOI] [PubMed] [Google Scholar]
  52. Sabatini B. L., Regehr W. G. Optical measurement of presynaptic calcium currents. Biophys J. 1998 Mar;74(3):1549–1563. doi: 10.1016/S0006-3495(98)77867-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Sabatini B. L., Svoboda K. Analysis of calcium channels in single spines using optical fluctuation analysis. Nature. 2000 Nov 30;408(6812):589–593. doi: 10.1038/35046076. [DOI] [PubMed] [Google Scholar]
  54. Schousboe A. Pharmacological and functional characterization of astrocytic GABA transport: a short review. Neurochem Res. 2000 Oct;25(9-10):1241–1244. doi: 10.1023/a:1007692012048. [DOI] [PubMed] [Google Scholar]
  55. Shepherd G. M., Harris K. M. Three-dimensional structure and composition of CA3-->CA1 axons in rat hippocampal slices: implications for presynaptic connectivity and compartmentalization. J Neurosci. 1998 Oct 15;18(20):8300–8310. doi: 10.1523/JNEUROSCI.18-20-08300.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Smith S. J. Do astrocytes process neural information? Prog Brain Res. 1992;94:119–136. doi: 10.1016/s0079-6123(08)61744-6. [DOI] [PubMed] [Google Scholar]
  57. Spacek J. Three-dimensional analysis of dendritic spines. III. Glial sheath. Anat Embryol (Berl) 1985;171(2):245–252. doi: 10.1007/BF00341419. [DOI] [PubMed] [Google Scholar]
  58. Stanley E. F. Presynaptic calcium channels and the depletion of synaptic cleft calcium ions. J Neurophysiol. 2000 Jan;83(1):477–482. doi: 10.1152/jn.2000.83.1.477. [DOI] [PubMed] [Google Scholar]
  59. Stiles J. R., Van Helden D., Bartol T. M., Jr, Salpeter E. E., Salpeter M. M. Miniature endplate current rise times less than 100 microseconds from improved dual recordings can be modeled with passive acetylcholine diffusion from a synaptic vesicle. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5747–5752. doi: 10.1073/pnas.93.12.5747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Syková E., Roitbak T., Mazel T., Simonová Z., Harvey A. R. Astrocytes, oligodendroglia, extracellular space volume and geometry in rat fetal brain grafts. Neuroscience. 1999;91(2):783–798. doi: 10.1016/s0306-4522(98)00603-4. [DOI] [PubMed] [Google Scholar]
  61. Takumi Y., Ramírez-León V., Laake P., Rinvik E., Ottersen O. P. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat Neurosci. 1999 Jul;2(7):618–624. doi: 10.1038/10172. [DOI] [PubMed] [Google Scholar]
  62. Trommershäuser J., Marienhagen J., Zippelius A. Stochastic model of central synapses: slow diffusion of transmitter interacting with spatially distributed receptors and transporters. J Theor Biol. 1999 May 7;198(1):101–120. doi: 10.1006/jtbi.1999.0905. [DOI] [PubMed] [Google Scholar]
  63. Uteshev V. V., Pennefather P. S. A mathematical description of miniature postsynaptic current generation at central nervous system synapses. Biophys J. 1996 Sep;71(3):1256–1266. doi: 10.1016/S0006-3495(96)79325-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Vassilev P. M., Mitchel J., Vassilev M., Kanazirska M., Brown E. M. Assessment of frequency-dependent alterations in the level of extracellular Ca2+ in the synaptic cleft. Biophys J. 1997 May;72(5):2103–2116. doi: 10.1016/S0006-3495(97)78853-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Ventura R., Harris K. M. Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci. 1999 Aug 15;19(16):6897–6906. doi: 10.1523/JNEUROSCI.19-16-06897.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Wadiche J. I., Arriza J. L., Amara S. G., Kavanaugh M. P. Kinetics of a human glutamate transporter. Neuron. 1995 May;14(5):1019–1027. doi: 10.1016/0896-6273(95)90340-2. [DOI] [PubMed] [Google Scholar]
  67. Wahl L. M., Pouzat C., Stratford K. J. Monte Carlo simulation of fast excitatory synaptic transmission at a hippocampal synapse. J Neurophysiol. 1996 Feb;75(2):597–608. doi: 10.1152/jn.1996.75.2.597. [DOI] [PubMed] [Google Scholar]
  68. Zador A., Koch C. Linearized models of calcium dynamics: formal equivalence to the cable equation. J Neurosci. 1994 Aug;14(8):4705–4715. doi: 10.1523/JNEUROSCI.14-08-04705.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]

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