Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling


Whereas glutamate transporters in glial cells and postsynaptic neurons contribute significantly to re-uptake of synaptically released transmitter, the functional role of presynaptic glutamate transporters is poorly understood. Here, we used electrophysiological recording to examine the functional properties of a presynaptic glutamate transporter in rat retinal rod bipolar cells and its role in regulating glutamatergic synaptic transmission between rod bipolar cells and amacrine cells. Release of glutamate activated the presynaptic transporter with a time course that suggested a perisynaptic localization. The transporter was also activated by spillover of glutamate from neighboring rod bipolar cells. By recording from pairs of rod bipolar cells and AII amacrine cells, we demonstrate that activation of the transporter-associated anion current hyperpolarizes the presynaptic terminal and thereby inhibits synaptic transmission by suppressing transmitter release. Given the evidence for presynaptic glutamate transporters, similar mechanisms could be of general importance for transmission in the nervous system.

Figure 1: Localization of a glutamate transporter at axon terminal of rod bipolar cells.
Figure 2: Kinetics and concentration-response relationship of glutamate transporter at rod bipolar axon terminals.
Figure 3: Synaptic release of glutamate activates the transporter in rod bipolar cells.
Figure 4: Spontaneous glutamate release activates the transporter in rod bipolar cells.
Figure 5: Spillover of glutamate between rod bipolar cells activates the transporter.
Figure 6: Action and interaction of excitatory and inhibitory conductances at rod bipolar cell axon terminals.
Figure 7: Activation of glutamate transporter in rod bipolar cell axon terminals suppresses synaptic transmission.


  1. 1

    Danbolt, N.C. Glutamate uptake. Prog. Neurobiol. 65, 1–105 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Chaudhry, F.A. et al. Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron 15, 711–720 (1995).

    CAS  Article  Google Scholar 

  3. 3

    Rothstein, J.D. et al. Localization of neuronal and glial glutamate transporters. Neuron 13, 713–725 (1994).

    CAS  Article  Google Scholar 

  4. 4

    Chen, W. et al. The glutamate transporter GLT1a is expressed in excitatory axon terminals of mature hippocampal neurons. J. Neurosci. 24, 1136–1148 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Eliasof, S. & Werblin, F. Characterization of the glutamate transporter in retinal cones of the tiger salamander. J. Neurosci. 13, 402–411 (1993).

    CAS  Article  Google Scholar 

  6. 6

    Gundersen, V., Danbolt, N.C., Ottersen, O.P. & Storm-Mathisen, J. Demonstration of glutamate/aspartate uptake activity in nerve endings by use of antibodies recognizing exogenous D-aspartate. Neuroscience 57, 97–111 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Hasegawa, J., Obara, T., Tanaka, K. & Tachibana, M. High-density presynaptic transporters are required for glutamate removal from the first visual synapse. Neuron 50, 63–74 (2006).

    CAS  Article  Google Scholar 

  8. 8

    He, Y., Janssen, W.G., Rothstein, J.D. & Morrison, J.H. Differential synaptic localization of the glutamate transporter EAAC1 and glutamate receptor subunit GluR2 in the rat hippocampus. J. Comp. Neurol. 418, 255–269 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Palmer, M.J., Taschenberger, H., Hull, C., Tremere, L. & von Gersdorff, H. Synaptic activation of presynaptic glutamate transporter currents in nerve terminals. J. Neurosci. 23, 4831–4841 (2003).

    CAS  Article  Google Scholar 

  10. 10

    Picaud, S., Larsson, H.P., Wellis, D.P., Lecar, H. & Werblin, F. Cone photoreceptors respond to their own glutamate release in the tiger salamander. Proc. Natl. Acad. Sci. USA 92, 9417–9421 (1995).

    CAS  Article  Google Scholar 

  11. 11

    Sarantis, M., Everett, K. & Attwell, D. A presynaptic action of glutamate at the cone output synapse. Nature 332, 451–453 (1988).

    CAS  Article  Google Scholar 

  12. 12

    Tachibana, M. & Kaneko, A. L-glutamate-induced depolarization in solitary photoreceptors: a process that might contribute to the interaction between photoreceptors in situ. Proc. Natl. Acad. Sci. USA 85, 5315–5319 (1988).

    CAS  Article  Google Scholar 

  13. 13

    Zerangue, N. & Kavanaugh, M.P. Flux coupling in a neuronal glutamate transporter. Nature 383, 634–637 (1996).

    CAS  Article  Google Scholar 

  14. 14

    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 375, 599–603 (1995).

    CAS  Article  Google Scholar 

  15. 15

    Wadiche, J.I., Amara, S.G. & Kavanaugh, M.P. Ion fluxes associated with excitatory amino acid transport. Neuron 15, 721–728 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Arriza, J.L., Eliasof, S., Kavanaugh, M.P. & Amara, S.G. Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc. Natl. Acad. Sci. USA 94, 4155–4160 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Protti, D.A. & Llano, I. Calcium currents and calcium signaling in rod bipolar cells of rat retinal slices. J. Neurosci. 18, 3715–3724 (1998).

    CAS  Article  Google Scholar 

  18. 18

    Shimamoto, K. et al. DL-threo-β-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters. Mol. Pharmacol. 53, 195–201 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Eliasof, S. & Jahr, C.E. Retinal glial cell glutamate transporter is coupled to an anionic conductance. Proc. Natl. Acad. Sci. USA 93, 4153–4158 (1996).

    CAS  Article  Google Scholar 

  20. 20

    Veruki, M.L., Mørkve, S.H. & Hartveit, E. Functional properties of spontaneous EPSCs and non-NMDA receptors in rod amacrine (AII) cells in the rat retina. J. Physiol. (Lond.) 549, 759–774 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Cavelier, P., Hamann, M., Rossi, D., Mobbs, P. & Attwell, D. Tonic excitation and inhibition of neurons: ambient transmitter sources and computational consequences. Prog. Biophys. Mol. Biol. 87, 3–16 (2005).

    CAS  Article  Google Scholar 

  22. 22

    von Gersdorff, H. & Matthews, G. Depletion and replenishment of vesicle pools at a ribbon-type synaptic terminal. J. Neurosci. 17, 1919–1927 (1997).

    CAS  Article  Google Scholar 

  23. 23

    von Gersdorff, H., Sakaba, T., Berglund, K. & Tachibana, M. Submillisecond kinetics of glutamate release from a sensory synapse. Neuron 21, 1177–1188 (1998).

    CAS  Article  Google Scholar 

  24. 24

    Singer, J.H. & Diamond, J.S. Vesicle depletion and synaptic depression at a mammalian ribbon synapse. J. Neurophysiol. 95, 3191–3198 (2006).

    CAS  Article  Google Scholar 

  25. 25

    Singer, J.H. & Diamond, J.S. Sustained Ca2+ entry elicits transient postsynaptic currents at a retinal ribbon synapse. J. Neurosci. 23, 10923–10933 (2003).

    CAS  Article  Google Scholar 

  26. 26

    Singer, J.H., Lassova, L., Vardi, N. & Diamond, J.S. Coordinated multivesicular release at a mammalian ribbon synapse. Nat. Neurosci. 7, 826–833 (2004).

    CAS  Article  Google Scholar 

  27. 27

    Bergles, D.E. & Jahr, C.E. Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron 19, 1297–1308 (1997).

    CAS  Article  Google Scholar 

  28. 28

    Otis, T.S. & Jahr, C.E. Anion currents and predicted glutamate flux through a neuronal glutamate transporter. J. Neurosci. 18, 7099–7110 (1998).

    CAS  Article  Google Scholar 

  29. 29

    Hartveit, E. Reciprocal synaptic interactions between rod bipolar cells and amacrine cells in the rat retina. J. Neurophysiol. 81, 2923–2936 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Rauen, T., Taylor, W.R., Kuhlbrodt, K. & Wiessner, M. High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in neurotransmitter clearance. Cell Tissue Res. 291, 19–31 (1998).

    CAS  Article  Google Scholar 

  31. 31

    Wadiche, J.I., Arriza, J.L., Amara, S.G. & Kavanaugh, M.P. Kinetics of a human glutamate transporter. Neuron 14, 1019–1027 (1995).

    CAS  Article  Google Scholar 

  32. 32

    Asztely, F., Erdemli, G. & Kullmann, D.M. Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake. Neuron 18, 281–293 (1997).

    CAS  Article  Google Scholar 

  33. 33

    Billups, D. & Attwell, D. Control of intracellular chloride concentration and GABA response polarity in rat retinal ON bipolar cells. J. Physiol. (Lond.) 545, 183–198 (2002).

    CAS  Article  Google Scholar 

  34. 34

    Duebel, J. et al. Two-photon imaging reveals somatodendritic chloride gradient in retinal ON-type bipolar cells expressing the biosensor clomeleon. Neuron 49, 81–94 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Yamashita, M. & Wässle, H. Reversal potential of GABA-induced currents in rod bipolar cells of the rat retina. Vis. Neurosci. 6, 399–401 (1991).

    CAS  Article  Google Scholar 

  36. 36

    Euler, T. & Masland, R.H. Light-evoked responses of bipolar cells in a mammalian retina. J. Neurophysiol. 83, 1817–1829 (2000).

    CAS  Article  Google Scholar 

  37. 37

    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. USA 94, 14821–14825 (1997).

    CAS  Article  Google Scholar 

  38. 38

    Bergles, D.E., Tzingounis, A.V. & Jahr, C.E. Comparison of coupled and uncoupled currents during glutamate uptake by GLT-1 transporters. J. Neurosci. 22, 10153–10162 (2002).

    CAS  Article  Google Scholar 

  39. 39

    Barbour, B. & Häusser, M. Intersynaptic diffusion of neurotransmitter. Trends Neurosci. 20, 377–384 (1997).

    CAS  Article  Google Scholar 

  40. 40

    Huang, Y.H. & Bergles, D.E. Glutamate transporters bring competition to the synapse. Curr. Opin. Neurobiol. 14, 346–352 (2004).

    CAS  Article  Google Scholar 

  41. 41

    Mørkve, S.H., Veruki, M.L. & Hartveit, E. Functional characteristics of non-NMDA-type ionotropic glutamate receptor channels in AII amacrine cells in rat retina. J. Physiol. (Lond.) 542, 147–165 (2002).

    Article  Google Scholar 

  42. 42

    Derouiche, A. & Rauen, T. Coincidence of L-glutamate/L-aspartate transporter (GLAST) and glutamine synthetase (GS) immunoreactions in retinal glia: evidence for coupling of GLAST and GS in transmitter clearance. J. Neurosci. Res. 42, 131–143 (1995).

    CAS  Article  Google Scholar 

  43. 43

    Pow, D.V. & Barnett, N.L. Developmental expression of excitatory amino acid transporter 5: a photoreceptor and bipolar cell glutamate transporter in rat retina. Neurosci. Lett. 280, 21–24 (2000).

    CAS  Article  Google Scholar 

  44. 44

    Rauen, T. & Kanner, B.I. Localization of the glutamate transporter GLT-1 in rat and macaque monkey retinae. Neurosci. Lett. 169, 137–140 (1994).

    CAS  Article  Google Scholar 

  45. 45

    Rauen, T., Rothstein, J.D. & Wässle, H. Differential expression of three glutamate transporter subtypes in the rat retina. Cell Tissue Res. 286, 325–336 (1996).

    CAS  Article  Google Scholar 

  46. 46

    Ward, M.M., Jobling, A.I., Puthussery, T., Foster, L.E. & Fletcher, E.L. Localization and expression of the glutamate transporter, excitatory amino acid transporter 4, within astrocytes of the rat retina. Cell Tissue Res. 315, 305–310 (2004).

    CAS  Article  Google Scholar 

  47. 47

    Tachibana, M. & Kaneko, A. γ-Aminobutyric acid exerts a local inhibitory action on the axon terminal of bipolar cells: evidence for negative feedback from amacrine cells. Proc. Natl. Acad. Sci. USA 84, 3501–3505 (1987).

    CAS  Article  Google Scholar 

  48. 48

    Palmer, M.J., Hull, C., Vigh, J. & von Gersdorff, H. Synaptic cleft acidification and modulation of short-term depression by exocytosed protons in retinal bipolar cells. J. Neurosci. 23, 11332–11341 (2003).

    CAS  Article  Google Scholar 

  49. 49

    Arnth-Jensen, N., Jabaudon, D. & Scanziani, M. Cooperation between independent hippocampal synapses is controlled by glutamate uptake. Nat. Neurosci. 5, 325–331 (2002).

    CAS  Article  Google Scholar 

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Financial support from the Norwegian Research Council (NFR 155397/310 and 161217/V40), the Meltzer fund (University of Bergen) and the Faculty of Medicine at the University of Bergen (fellowships for M.L.V. and S.H.M.) is gratefully acknowledged.

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Correspondence to Espen Hartveit.

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Veruki, M., Mørkve, S. & Hartveit, E. Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling. Nat Neurosci 9, 1388–1396 (2006).

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