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. 2002 Jul;83(1):125–134. doi: 10.1016/S0006-3495(02)75154-0

Asymmetry of glia near central synapses favors presynaptically directed glutamate escape.

Knut Petter Lehre 1, Dmitri A Rusakov 1
PMCID: PMC1302132  PMID: 12080105

Abstract

Recent findings demonstrate that synaptically released excitatory neurotransmitter glutamate activates receptors outside the immediate synaptic cleft and that the extent of such extrasynaptic actions is regulated by the high affinity glutamate uptake. The bulk of glutamate transporter systems are evenly distributed in the synaptic neuropil, and it is generally assumed that glutamate escaping the cleft affects pre- and postsynaptic receptors to a similar degree. To test whether this is indeed the case, we use quantitative electron microscopy and establish the stochastic pattern of glial occurrence in the three-dimensional (3D) vicinity of two common types of excitatory central synapses, stratum radiatum synapses in hippocampus and parallel fiber synapses in cerebellum. We find that the occurrence of glia postsynaptically is strikingly higher (3-4-fold) than presynaptically, in both types of synapses. To address the functional consequences of this asymmetry, we simulate diffusion and transport of synaptically released glutamate in these two brain areas using a detailed 3D compartmental model of the extracellular space with glutamate transporters arranged unevenly, in accordance with the obtained experimental data. The results predict that glutamate escaping the synaptic cleft is 2-4 times more likely to activate presynaptic compared to postsynaptic receptors. Simulations also show that postsynaptic neuronal transporters (EAAT4 type) at dendritic spines of cerebellar Purkinje cells exaggerate this asymmetry further. Our data suggest that the perisynaptic environment of these common central synapses favors fast presynaptic feedback in the information flow while preserving the specificity of the postsynaptic input.

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Selected References

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  1. 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]
  2. 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]
  3. 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]
  4. Barbour B., Häusser M. Intersynaptic diffusion of neurotransmitter. Trends Neurosci. 1997 Sep;20(9):377–384. doi: 10.1016/s0166-2236(96)20050-5. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Batchelor A. M., Madge D. J., Garthwaite J. Synaptic activation of metabotropic glutamate receptors in the parallel fibre-Purkinje cell pathway in rat cerebellar slices. Neuroscience. 1994 Dec;63(4):911–915. doi: 10.1016/0306-4522(94)90558-4. [DOI] [PubMed] [Google Scholar]
  7. Bergles D. E., Dzubay J. A., Jahr C. E. Glutamate transporter currents in bergmann glial cells follow the time course of extrasynaptic glutamate. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14821–14825. doi: 10.1073/pnas.94.26.14821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. Bergles D. E., Jahr C. E. Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron. 1997 Dec;19(6):1297–1308. doi: 10.1016/s0896-6273(00)80420-1. [DOI] [PubMed] [Google Scholar]
  10. Brasnjo G., Otis T. S. Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression. Neuron. 2001 Aug 30;31(4):607–616. doi: 10.1016/s0896-6273(01)00377-4. [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. Chaudhry F. A., Lehre K. P., van Lookeren Campagne M., Ottersen O. P., Danbolt N. C., Storm-Mathisen J. Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron. 1995 Sep;15(3):711–720. doi: 10.1016/0896-6273(95)90158-2. [DOI] [PubMed] [Google Scholar]
  13. Clark B. A., Barbour B. Currents evoked in Bergmann glial cells by parallel fibre stimulation in rat cerebellar slices. J Physiol. 1997 Jul 15;502(Pt 2):335–350. doi: 10.1111/j.1469-7793.1997.335bk.x. [DOI] [PMC free article] [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. Danbolt N. C. Glutamate uptake. Prog Neurobiol. 2001 Sep;65(1):1–105. doi: 10.1016/s0301-0082(00)00067-8. [DOI] [PubMed] [Google Scholar]
  16. Dehnes Y., Chaudhry F. A., Ullensvang K., Lehre K. P., Storm-Mathisen J., Danbolt N. C. The glutamate transporter EAAT4 in rat cerebellar Purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J Neurosci. 1998 May 15;18(10):3606–3619. doi: 10.1523/JNEUROSCI.18-10-03606.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Diamond J. S., Bergles D. E., Jahr C. E. Glutamate release monitored with astrocyte transporter currents during LTP. Neuron. 1998 Aug;21(2):425–433. doi: 10.1016/s0896-6273(00)80551-6. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Diamond J. S. Neuronal glutamate transporters limit activation of NMDA receptors by neurotransmitter spillover on CA1 pyramidal cells. J Neurosci. 2001 Nov 1;21(21):8328–8338. doi: 10.1523/JNEUROSCI.21-21-08328.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fairman W. A., Vandenberg R. J., Arriza J. L., Kavanaugh M. P., Amara S. G. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature. 1995 Jun 15;375(6532):599–603. doi: 10.1038/375599a0. [DOI] [PubMed] [Google Scholar]
  21. Furuta A., Martin L. J., Lin C. L., Dykes-Hoberg M., Rothstein J. D. Cellular and synaptic localization of the neuronal glutamate transporters excitatory amino acid transporter 3 and 4. Neuroscience. 1997 Dec;81(4):1031–1042. doi: 10.1016/s0306-4522(97)00252-2. [DOI] [PubMed] [Google Scholar]
  22. Harvey R. J., Napper R. M. Quantitative study of granule and Purkinje cells in the cerebellar cortex of the rat. J Comp Neurol. 1988 Aug 8;274(2):151–157. doi: 10.1002/cne.902740202. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Klöckner U., Storck T., Conradt M., Stoffel W. Functional properties and substrate specificity of the cloned L-glutamate/L-aspartate transporter GLAST-1 from rat brain expressed in Xenopus oocytes. J Neurosci. 1994 Oct;14(10):5759–5765. doi: 10.1523/JNEUROSCI.14-10-05759.1994. [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. 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]
  27. 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]
  28. Levy L. M., Warr O., Attwell D. Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. J Neurosci. 1998 Dec 1;18(23):9620–9628. doi: 10.1523/JNEUROSCI.18-23-09620.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Luján R., Roberts J. D., Shigemoto R., Ohishi H., Somogyi P. Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1 alpha, mGluR2 and mGluR5, relative to neurotransmitter release sites. J Chem Neuroanat. 1997 Oct;13(4):219–241. doi: 10.1016/s0891-0618(97)00051-3. [DOI] [PubMed] [Google Scholar]
  30. Lüscher C., Malenka R. C., Nicoll R. A. Monitoring glutamate release during LTP with glial transporter currents. Neuron. 1998 Aug;21(2):435–441. doi: 10.1016/s0896-6273(00)80552-8. [DOI] [PubMed] [Google Scholar]
  31. Mazel T., Simonová Z., Syková E. Diffusion heterogeneity and anisotropy in rat hippocampus. Neuroreport. 1998 May 11;9(7):1299–1304. doi: 10.1097/00001756-199805110-00008. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Min M. Y., Rusakov D. A., Kullmann D. M. Activation of AMPA, kainate, and metabotropic receptors at hippocampal mossy fiber synapses: role of glutamate diffusion. Neuron. 1998 Sep;21(3):561–570. doi: 10.1016/s0896-6273(00)80566-8. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Oliet S. H., Piet R., Poulain D. A. Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science. 2001 May 4;292(5518):923–926. doi: 10.1126/science.1059162. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. 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]
  38. Otis T. S., Kavanaugh M. P., Jahr C. E. Postsynaptic glutamate transport at the climbing fiber-Purkinje cell synapse. Science. 1997 Sep 5;277(5331):1515–1518. doi: 10.1126/science.277.5331.1515. [DOI] [PubMed] [Google Scholar]
  39. Pines G., Danbolt N. C., Bjørås M., Zhang Y., Bendahan A., Eide L., Koepsell H., Storm-Mathisen J., Seeberg E., Kanner B. I. Cloning and expression of a rat brain L-glutamate transporter. Nature. 1992 Dec 3;360(6403):464–467. doi: 10.1038/360464a0. [DOI] [PubMed] [Google Scholar]
  40. Pérez-Pinzón M. A., Tao L., Nicholson C. Extracellular potassium, volume fraction, and tortuosity in rat hippocampal CA1, CA3, and cortical slices during ischemia. J Neurophysiol. 1995 Aug;74(2):565–573. doi: 10.1152/jn.1995.74.2.565. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. 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]
  43. 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]
  44. Rusakov D. A. The role of perisynaptic glial sheaths in glutamate spillover and extracellular Ca(2+) depletion. Biophys J. 2001 Oct;81(4):1947–1959. doi: 10.1016/S0006-3495(01)75846-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Scanziani M., Malenka R. C., Nicoll R. A. Role of intercellular interactions in heterosynaptic long-term depression. Nature. 1996 Apr 4;380(6573):446–450. doi: 10.1038/380446a0. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. 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]
  48. 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]
  49. 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]
  50. Uteshev V. V., Patlak J. B., Pennefather P. S. Analysis and implications of equivalent uniform approximations of nonuniform unitary synaptic systems. Biophys J. 2000 Dec;79(6):2825–2839. doi: 10.1016/S0006-3495(00)76521-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. 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]
  52. 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]
  53. Vogt K. E., Nicoll R. A. Glutamate and gamma-aminobutyric acid mediate a heterosynaptic depression at mossy fiber synapses in the hippocampus. Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):1118–1122. doi: 10.1073/pnas.96.3.1118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. 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]
  55. Wadiche J. I., Kavanaugh M. P. Macroscopic and microscopic properties of a cloned glutamate transporter/chloride channel. J Neurosci. 1998 Oct 1;18(19):7650–7661. doi: 10.1523/JNEUROSCI.18-19-07650.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. 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]
  57. Xu-Friedman M. A., Harris K. M., Regehr W. G. Three-dimensional comparison of ultrastructural characteristics at depressing and facilitating synapses onto cerebellar Purkinje cells. J Neurosci. 2001 Sep 1;21(17):6666–6672. doi: 10.1523/JNEUROSCI.21-17-06666.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]

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