Presynaptic glutamate receptors: physiological functions and mechanisms of action

Key Points

  • Glutamate is the main excitatory neurotransmitter in the brain and activates a variety of ionotropic and metabotropic receptors (iGluRs and mGluRs, respectively) located postsynaptically. Recent studies have highlighted the physiological part played by presynaptic iGluRs and mGluRs in regulating synaptic transmission, both as autoreceptors and as heteroreceptors.

  • The activation of presynaptic GluRs depends on their localization in relation to the source of glutamate, their affinity for glutamate and the spatiotemporal features of glutamate release in the extracellular space. These factors define the distinct physiological conditions under which presynaptic GluRs can be activated.

  • The glutamate that activates presynaptic GluRs can originate from the same terminals as the receptors, from neighbouring synapses, from retrograde release from active somatodendritic compartments or glial cells and from basal release into the extracellular space.

  • Presynaptic iGluRs often facilitate neurotransmission and have short-lived effects. They achieve this through mechanisms that involve the depolarization of the nerve terminal, the direct modulation of Ca2+ channels, the direct influx of Ca2+ through the receptor channel, the induction of Ca2+-induced Ca2+ release from internal stores or the synthesis of nitric oxide. Prolonged receptor activation can trigger an as yet unclear G-protein-dependent signalling cascade that depresses release.

  • Presynaptic mGluRs generally depress neurotransmitter release by inhibiting Ca2+ channels, activating K+ conductances, modulating the exocytotic machinery or modulating the levels of cyclic AMP. They can also increase neurotransmitter release by activating Ca2+-induced Ca2+ release.

  • Presynaptic GluRs can be developmentally regulated, leading to a reduction or loss of function. This generally coincides with critical periods of development that lead to alterations in the rules that govern synaptic plasticity.

  • Presynaptic GluRs finely tune synaptic network activity either in a local homosynaptic manner or by sensing the activity of neighbouring synapses. Presynaptic GluRs can support short- or long-term changes in synaptic transmission and plasticity and potentially play an important part in higher brain function.


Glutamate acts on postsynaptic glutamate receptors to mediate excitatory communication between neurons. The discovery that additional presynaptic glutamate receptors can modulate neurotransmitter release has added complexity to the way we view glutamatergic synaptic transmission. Here we review evidence of a physiological role for presynaptic glutamate receptors in neurotransmitter release. We compare the physiological roles of ionotropic and metabotropic glutamate receptors in short- and long-term regulation of synaptic transmission. Furthermore, we discuss the physiological conditions that are necessary for their activation, the source of the glutamate that activates them, their mechanisms of action and their involvement in higher brain function.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Physiological functions of presynaptic GluRs at hippocampal mossy fibre synapses.
Figure 2: Regulation by presynaptic GluRs of inhibitory synaptic transmission onto Purkinje cells.
Figure 3: Modes of activation of presynaptic GluRs.
Figure 4: Mechanisms of action of presynaptic GluRs.


  1. 1

    Agrawal, S. & Evans, R. The primary afferent depolarizing action of kainate in the rat. Brit. J. Pharmacol. 87, 345–355 (1986).

    CAS  Google Scholar 

  2. 2

    Chittajallu, R., Braithwaite, S. P., Clarke, V. R. & Henley, J. M. Kainate receptors: subunits, synaptic localization and function. Trends Pharmacol. Sci. 20, 26–35 (1999).

    CAS  PubMed  Google Scholar 

  3. 3

    Frerking, M. & Nicoll, R. A. Synaptic kainate receptors. Curr. Opin. Neurobiol. 10, 342–351 (2000).

    CAS  PubMed  Google Scholar 

  4. 4

    Huettner, J. E. Kainate receptors and synaptic transmission. Prog. Neurobiol. 70, 387–407 (2003).

    CAS  PubMed  Google Scholar 

  5. 5

    Lerma, J. Roles and rules of kainate receptors in synaptic transmission. Nature Rev. Neurosci. 4, 481–495 (2003).

    CAS  Google Scholar 

  6. 6

    Frerking, M., Petersen, C. C. & Nicoll, R. A. Mechanisms underlying kainate receptor-mediated disinhibition in the hippocampus. Proc. Natl Acad. Sci. USA 96, 12917–12922 (1999).

    CAS  PubMed  Google Scholar 

  7. 7

    Chergui, K., Bouron, A., Normand, E. & Mulle, C. Functional GluR6 kainate receptors in the striatum: indirect downregulation of synaptic transmission. J. Neurosci. 20, 2175–2182 (2000).

    CAS  PubMed  Google Scholar 

  8. 8

    Engelman, H. S. & MacDermott, A. B. Presynaptic ionotropic receptors and control of transmitter release. Nature Rev. Neurosci. 5, 135–145 (2004).

    CAS  Google Scholar 

  9. 9

    Sun, H. Y. & Dobrunz, L. E. Presynaptic kainate receptor activation is a novel mechanism for target cell-specific short-term facilitation at Schaffer collateral synapses. J. Neurosci. 26, 10796–10807 (2006).

    CAS  PubMed  Google Scholar 

  10. 10

    Delaney, A. J. & Jahr, C. E. Kainate receptors differentially regulate release at two parallel fiber synapses. Neuron 36, 475–482 (2002).

    CAS  Google Scholar 

  11. 11

    Lauri, S. E. et al. A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP. Neuron 32, 697–709 (2001).

    CAS  PubMed  Google Scholar 

  12. 12

    Pinheiro, P. S. et al. GluR7 is an essential subunit of presynaptic kainate autoreceptors at hippocampal mossy fiber synapses. Proc. Natl Acad. Sci. USA 104, 12181–12186 (2007). This study provided the first demonstration of a physiological function for the GluR7 subunit of KARs in the brain and suggested that presynaptic autoreceptors are located close to glutamate release sites.

    CAS  PubMed  Google Scholar 

  13. 13

    Schmitz, D., Frerking, M. & Nicoll, R. A. Synaptic activation of presynaptic kainate receptors on hippocampal mossy fiber synapses. Neuron 27, 327–338 (2000).

    CAS  Google Scholar 

  14. 14

    Kidd, F. L., Coumis, U., Collingridge, G. L., Crabtree, J. W. & Isaac, J. T. A presynaptic kainate receptor is involved in regulating the dynamic properties of thalamocortical synapses during development. Neuron 34, 635–646 (2002).

    CAS  PubMed  Google Scholar 

  15. 15

    Contractor, A., Swanson, G. & Heinemann, S. F. Kainate receptors are involved in short- and long-term plasticity at mossy fiber synapses in the hippocampus. Neuron 29, 209–216 (2001). This study showed that presynaptic KARs have a critical role in multiple forms of hippocampal mossy fibre synaptic plasticity.

    CAS  PubMed  Google Scholar 

  16. 16

    Henze, D. A., Wittner, L. & Buzsaki, G. Single granule cells reliably discharge targets in the hippocampal CA3 network in vivo. Nature Neurosci. 5, 790–795 (2002).

    CAS  Google Scholar 

  17. 17

    Contractor, A. et al. Loss of kainate receptor-mediated heterosynaptic facilitation of mossy-fiber synapses in KA2-/- mice. J. Neurosci. 23, 422–429 (2003).

    CAS  Google Scholar 

  18. 18

    Schmitz, D., Mellor, J. & Nicoll, R. A. Presynaptic kainate receptor mediation of frequency facilitation at hippocampal mossy fiber synapses. Science 291, 1972–1976 (2001). This study gave the first demonstration that presynaptic KARs contribute significantly to the high dynamic range of hippocampal mossy fibre synapses, which was previously thought to be an intrinsic property of these synapses.

    CAS  PubMed  Google Scholar 

  19. 19

    Lauri, S. E. et al. Endogenous activation of kainate receptors regulates glutamate release and network activity in the developing hippocampus. J. Neurosci. 25, 4473–4484 (2005).

    CAS  PubMed  Google Scholar 

  20. 20

    Lauri, S. E. et al. Functional maturation of CA1 synapses involves activity-dependent loss of tonic kainate receptor-mediated inhibition of glutamate release. Neuron 50, 415–429 (2006).

    CAS  PubMed  Google Scholar 

  21. 21

    Ali, A. B., Rossier, J., Staiger, J. F. & Audinat, E. Kainate receptors regulate unitary IPSCs elicited in pyramidal cells by fast-spiking interneurons in the neocortex. J. Neurosci. 21, 2992–2999 (2001).

    CAS  PubMed  Google Scholar 

  22. 22

    Jiang, L., Xu, J., Nedergaard, M. & Kang, J. A kainate receptor increases the efficacy of GABAergic synapses. Neuron 30, 503–513 (2001). This study showed that the activation of presynaptic KARs by ambient glutamate can increase the release of GABA and thereby balance excitation.

    CAS  PubMed  Google Scholar 

  23. 23

    Kerchner, G. A., Wang, G. D., Qiu, C. S., Huettner, J. E. & Zhuo, M. Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn: an ionotropic mechanism. Neuron 32, 477–488 (2001).

    CAS  PubMed  Google Scholar 

  24. 24

    Min, M. Y., Melyan, Z. & Kullmann, D. M. Synaptically released glutamate reduces gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus via kainate receptors. Proc. Natl Acad. Sci. USA 96, 9932–9937 (1999).

    CAS  PubMed  Google Scholar 

  25. 25

    Ren, M., Yoshimura, Y., Takada, N., Horibe, S. & Komatsu, Y. Specialized inhibitory synaptic actions between nearby neocortical pyramidal neurons. Science 316, 758–761 (2007). This study demonstrated that cortical excitatory neurons can generate inhibition through axo-axonic contacts with GABAergic terminals without the need for somatic interneuron firing.

    CAS  PubMed  Google Scholar 

  26. 26

    Berretta, N. & Jones, R. S. Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex. Neuroscience 75, 339–344 (1996).

    CAS  PubMed  Google Scholar 

  27. 27

    Woodhall, G., Evans, D. I., Cunningham, M. O. & Jones, R. S. NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons. J. Neurophysiol. 86, 1644–1651 (2001).

    CAS  PubMed  Google Scholar 

  28. 28

    Yang, J., Woodhall, G. L. & Jones, R. S. Tonic facilitation of glutamate release by presynaptic NR2B-containing NMDA receptors is increased in the entorhinal cortex of chronically epileptic rats. J. Neurosci. 26, 406–410 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Li, Y. H. & Han, T. Z. Glycine binding sites of presynaptic NMDA receptors may tonically regulate glutamate release in the rat visual cortex. J. Neurophysiol. 97, 817–823 (2007).

    CAS  PubMed  Google Scholar 

  30. 30

    Sjostrom, P. J., Turrigiano, G. G. & Nelson, S. B. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron 39, 641–654 (2003). This paper described a novel form of coincidence detection that is strictly dependent on the combined activation of presynaptic NMDARs and presynaptic CB1Rs with resultant LTD of synaptic transmission.

    PubMed  Google Scholar 

  31. 31

    Corlew, R., Wang, Y., Ghermazien, H., Erisir, A. & Philpot, B. D. Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression. J. Neurosci. 27, 9835–9845 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Jourdain, P. et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nature Neurosci. 10, 331–339 (2007). This study combined morphological and functional evidence to describe the control of synaptic activity through presynaptic iGluRs activated by glutamate released from astrocytes.

    CAS  PubMed  Google Scholar 

  33. 33

    Duguid, I. C. & Smart, T. G. Retrograde activation of presynaptic NMDA receptors enhances GABA release at cerebellar interneuron–Purkinje cell synapses. Nature Neurosci. 7, 525–533 (2004). This study described the activation of presynaptic NMDARs on inhibitory terminals by the retrograde release of glutamate from depolarized Purkinje cells, leading to an increase in the inhibitory drive onto these cells.

    CAS  PubMed  Google Scholar 

  34. 34

    Glitsch, M. & Marty, A. Presynaptic effects of NMDA in cerebellar Purkinje cells and interneurons. J. Neurosci. 19, 511–519 (1999).

    CAS  PubMed  Google Scholar 

  35. 35

    Huang, H. & Bordey, A. Glial glutamate transporters limit spillover activation of presynaptic NMDA receptors and influence synaptic inhibition of Purkinje neurons. J. Neurosci. 24, 5659–5669 (2004).

    CAS  PubMed  Google Scholar 

  36. 36

    Liu, S. J. & Lachamp, P. The activation of excitatory glutamate receptors evokes a long-lasting increase in the release of GABA from cerebellar stellate cells. J. Neurosci. 26, 9332–9339 (2006).

    CAS  PubMed  Google Scholar 

  37. 37

    Mameli, M., Carta, M., Partridge, L. D. & Valenzuela, C. F. Neurosteroid-induced plasticity of immature synapses via retrograde modulation of presynaptic NMDA receptors. J. Neurosci. 25, 2285–2294 (2005).

    CAS  PubMed  Google Scholar 

  38. 38

    Takago, H., Nakamura, Y. & Takahashi, T. G protein-dependent presynaptic inhibition mediated by AMPA receptors at the calyx of Held. Proc. Natl Acad. Sci. USA 102, 7368–7373 (2005).

    CAS  PubMed  Google Scholar 

  39. 39

    Rusakov, D. A., Saitow, F., Lehre, K. P. & Konishi, S. Modulation of presynaptic Ca2+ entry by AMPA receptors at individual GABAergic synapses in the cerebellum. J. Neurosci. 25, 4930–4940 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Satake, S., Saitow, F., Yamada, J. & Konishi, S. Synaptic activation of AMPA receptors inhibits GABA release from cerebellar interneurons. Nature Neurosci. 3, 551–558 (2000).

    CAS  PubMed  Google Scholar 

  41. 41

    Satake, S. et al. Characterization of AMPA receptors targeted by the climbing fiber transmitter mediating presynaptic inhibition of GABAergic transmission at cerebellar interneuron-Purkinje cell synapses. J. Neurosci. 26, 2278–2289 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Liu, S. J. Biphasic modulation of GABA release from stellate cells by glutamatergic receptor subtypes. J. Neurophysiol. 98, 550–556 (2007).

    CAS  PubMed  Google Scholar 

  43. 43

    Russo, R. E., Delgado-Lezama, R. & Hounsgaard, J. Dorsal root potential produced by a TTX-insensitive micro-circuitry in the turtle spinal cord. J. Physiol. 528, 115–122 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Lee, C. J. et al. Functional expression of AMPA receptors on central terminals of rat dorsal root ganglion neurons and presynaptic inhibition of glutamate release. Neuron 35, 135–146 (2002).

    CAS  PubMed  Google Scholar 

  45. 45

    Conn, P. J. & Pin, J. P. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37, 205–237 (1997).

    CAS  PubMed  Google Scholar 

  46. 46

    Anwyl, R. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res. Brain Res. Rev. 29, 83–120 (1999).

    CAS  PubMed  Google Scholar 

  47. 47

    Takahashi, M. & Alford, S. The requirement of presynaptic metabotropic glutamate receptors for the maintenance of locomotion. J. Neurosci. 22, 3692–3699 (2002).

    CAS  PubMed  Google Scholar 

  48. 48

    Cochilla, A. J. & Alford, S. Metabotropic glutamate receptor-mediated control of neurotransmitter release. Neuron 20, 1007–1016 (1998).

    CAS  PubMed  Google Scholar 

  49. 49

    Schoepp, D. D. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 299, 12–20 (2001).

    CAS  PubMed  Google Scholar 

  50. 50

    Scanziani, M., Salin, P. A., Vogt, K. E., Malenka, R. C. & Nicoll, R. A. Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors. Nature 385, 630–634 (1997). This study showed that extracellular glutamate build-up at hippocampal mossy fibre synapses leads to activity-dependent negative feedback through presynaptic mGluRs that regulates synaptic transmission.

    CAS  PubMed  Google Scholar 

  51. 51

    Mateo, Z. & Porter, J. T. Group II metabotropic glutamate receptors inhibit glutamate release at thalamocortical synapses in the developing somatosensory cortex. Neuroscience 146, 1062–1072 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    von Gersdorff, H., Schneggenburger, R., Weis, S. & Neher, E. Presynaptic depression at a calyx synapse: the small contribution of metabotropic glutamate receptors. J. Neurosci. 17, 8137–8146 (1997).

    CAS  PubMed  Google Scholar 

  53. 53

    Semyanov, A. & Kullmann, D. M. Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Neuron 25, 663–672 (2000).

    CAS  PubMed  Google Scholar 

  54. 54

    Ferraguti, F. & Shigemoto, R. Metabotropic glutamate receptors. Cell Tissue Res. 326, 483–504 (2006).

    CAS  Google Scholar 

  55. 55

    Sansig, G. et al. Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. J. Neurosci. 21, 8734–8745 (2001).

    CAS  PubMed  Google Scholar 

  56. 56

    Billups, B., Graham, B. P., Wong, A. Y. & Forsythe, I. D. Unmasking group III metabotropic glutamate autoreceptor function at excitatory synapses in the rat CNS. J. Physiol. 565, 885–896 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Pekhletski, R. et al. Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. J. Neurosci. 16, 6364–6373 (1996).

    CAS  PubMed  Google Scholar 

  58. 58

    Schrader, L. A. & Tasker, J. G. Presynaptic modulation by metabotropic glutamate receptors of excitatory and inhibitory synaptic inputs to hypothalamic magnocellular neurons. J. Neurophysiol. 77, 527–536 (1997).

    CAS  PubMed  Google Scholar 

  59. 59

    Mitchell, S. J. & Silver, R. A. Glutamate spillover suppresses inhibition by activating presynaptic mGluRs. Nature 404, 498–502 (2000). This study showed that glutamate spillover from excitatory terminals under physiological conditions activates presynaptic mGluRs on nearby inhibitory terminals to reduce GABA release and, therefore, increase the efficacy of the active excitatory fibres.

    CAS  PubMed  Google Scholar 

  60. 60

    Chu, Z. & Moenter, S. M. Endogenous activation of metabotropic glutamate receptors modulates GABAergic transmission to gonadotropin-releasing hormone neurons and alters their firing rate: a possible local feedback circuit. J. Neurosci. 25, 5740–5749 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    van den Pol, A. N., Gao, X. B., Patrylo, P. R., Ghosh, P. K. & Obrietan, K. Glutamate inhibits GABA excitatory activity in developing neurons. J. Neurosci. 18, 10749–10761 (1998).

    CAS  PubMed  Google Scholar 

  62. 62

    Browning, K. N. & Travagli, R. A. Functional organization of presynaptic metabotropic glutamate receptors in vagal brainstem circuits. J. Neurosci. 27, 8979–8988 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Schmitz, D., Mellor, J., Breustedt, J. & Nicoll, R. A. Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation. Nature Neurosci. 6, 1058–1063 (2003).

    CAS  PubMed  Google Scholar 

  64. 64

    Humeau, Y., Shaban, H., Bissiere, S. & Luthi, A. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature 426, 841–845 (2003). This study demonstrated the existence of a presynaptic form of associative LTP in the amygdala that depends on the activation of presynaptic NMDARs.

    CAS  PubMed  Google Scholar 

  65. 65

    Samson, R. D. & Pare, D. Activity-dependent synaptic plasticity in the central nucleus of the amygdala. J. Neurosci. 25, 1847–1855 (2005).

    CAS  PubMed  Google Scholar 

  66. 66

    Duguid, I. & Sjostrom, P. J. Novel presynaptic mechanisms for coincidence detection in synaptic plasticity. Curr. Opin. Neurobiol. 16, 312–322 (2006).

    CAS  PubMed  Google Scholar 

  67. 67

    Bender, V. A., Bender, K. J., Brasier, D. J. & Feldman, D. E. Two coincidence detectors for spike timing-dependent plasticity in somatosensory cortex. J. Neurosci. 26, 4166–4177 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Casado, M., Isope, P. & Ascher, P. Involvement of presynaptic N-methyl-D-aspartate receptors in cerebellar long-term depression. Neuron 33, 123–130 (2002).

    CAS  PubMed  Google Scholar 

  69. 69

    Shin, J. H. & Linden, D. J. An NMDA receptor/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal. J. Neurophysiol. 94, 4281–4289 (2005).

    CAS  PubMed  Google Scholar 

  70. 70

    Safo, P. K. & Regehr, W. G. Endocannabinoids control the induction of cerebellar LTD. Neuron 48, 647–659 (2005).

    CAS  Google Scholar 

  71. 71

    Lien, C. C., Mu, Y., Vargas-Caballero, M. & Poo, M. M. Visual stimuli-induced LTD of GABAergic synapses mediated by presynaptic NMDA receptors. Nature Neurosci. 9, 372–380 (2006). This was the first study to show, in vivo , the induction of a presynaptic LTD of GABAergic synapses onto tectal neurons, through activation of presynaptic glutamate receptors by spillover during visual stimulation.

    CAS  PubMed  Google Scholar 

  72. 72

    Malenka, R. C. & Bear, M. F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).

    CAS  Google Scholar 

  73. 73

    Manahan-Vaughan, D. Group 1 and 2 metabotropic glutamate receptors play differential roles in hippocampal long-term depression and long-term potentiation in freely moving rats. J. Neurosci. 17, 3303–3311 (1997).

    CAS  PubMed  Google Scholar 

  74. 74

    Huang, L. Q., Rowan, M. J. & Anwyl, R. mGluR II agonist inhibition of LTP induction, and mGluR II antagonist inhibition of LTD induction, in the dentate gyrus in vitro. Neuroreport 8, 687–693 (1997).

    CAS  PubMed  Google Scholar 

  75. 75

    Poschel, B., Wroblewska, B., Heinemann, U. & Manahan-Vaughan, D. The metabotropic glutamate receptor mGluR3 is critically required for hippocampal long-term depression and modulates long-term potentiation in the dentate gyrus of freely moving rats. Cereb. Cortex 15, 1414–1423 (2005).

    PubMed  Google Scholar 

  76. 76

    Otani, S., Auclair, N., Desce, J. M., Roisin, M. P. & Crepel, F. Dopamine receptors and groups I and II mGluRs cooperate for long-term depression induction in rat prefrontal cortex through converging postsynaptic activation of MAP kinases. J. Neurosci. 19, 9788–9802 (1999).

    CAS  PubMed  Google Scholar 

  77. 77

    Kaschel, T., Schubert, M. & Albrecht, D. Long-term depression in horizontal slices of the rat lateral amygdala. Synapse 53, 141–150 (2004).

    CAS  PubMed  Google Scholar 

  78. 78

    Lin, H. C., Wang, S. J., Luo, M. Z. & Gean, P. W. Activation of group II metabotropic glutamate receptors induces long-term depression of synaptic transmission in the rat amygdala. J. Neurosci. 20, 9017–9024 (2000).

    CAS  PubMed  Google Scholar 

  79. 79

    Robbe, D., Alonso, G., Chaumont, S., Bockaert, J. & Manzoni, O. J. Role of P/Q-Ca2+ channels in metabotropic glutamate receptor 2/3-dependent presynaptic long-term depression at nucleus accumbens synapses. J. Neurosci. 22, 4346–4356 (2002).

    CAS  PubMed  Google Scholar 

  80. 80

    Kobayashi, K., Manabe, T. & Takahashi, T. Presynaptic long-term depression at the hippocampal mossy fiber-CA3 synapse. Science 273, 648–650 (1996).

    CAS  PubMed  Google Scholar 

  81. 81

    Yokoi, M. et al. Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2. Science 273, 645–647 (1996).

    CAS  PubMed  Google Scholar 

  82. 82

    Pelkey, K. A., Lavezzari, G., Racca, C., Roche, K. W. & McBain, C. J. mGluR7 is a metaplastic switch controlling bidirectional plasticity of feedforward inhibition. Neuron 46, 89–102 (2005).

    CAS  PubMed  Google Scholar 

  83. 83

    Pelkey, K. A., Topolnik, L., Lacaille, J. C. & McBain, C. J. Compartmentalized Ca2+ channel regulation at divergent mossy-fiber release sites underlies target cell-dependent plasticity. Neuron 52, 497–510 (2006). This study showed that the target-cell-specific localization of presynaptic mGluR7 receptors onto divergent mossy fibre synapses provides a compartmentalized regulation of presynaptic function and plasticity.

    CAS  PubMed  Google Scholar 

  84. 84

    Laezza, F., Doherty, J. J. & Dingledine, R. Long-term depression in hippocampal interneurons: joint requirement for pre- and postsynaptic events. Science 285, 1411–1414 (1999).

    CAS  PubMed  Google Scholar 

  85. 85

    Kobayashi, K., Manabe, T. & Takahashi, T. Calcium-dependent mechanisms involved in presynaptic long-term depression at the hippocampal mossy fibre-CA3 synapse. Eur. J. Neurosci. 11, 1633–1638 (1999).

    CAS  PubMed  Google Scholar 

  86. 86

    Chen, Y. L., Huang, C. C. & Hsu, K. S. Time-dependent reversal of long-term potentiation by low-frequency stimulation at the hippocampal mossy fiber-CA3 synapses. J. Neurosci. 21, 3705–3714 (2001).

    CAS  PubMed  Google Scholar 

  87. 87

    Aoki, C., Venkatesan, C., Go, C. G., Mong, J. A. & Dawson, T. M. Cellular and subcellular localization of NMDA-R1 subunit immunoreactivity in the visual cortex of adult and neonatal rats. J. Neurosci. 14, 5202–5222 (1994).

    CAS  PubMed  Google Scholar 

  88. 88

    DeBiasi, S., Minelli, A., Melone, M. & Conti, F. Presynaptic NMDA receptors in the neocortex are both auto- and heteroreceptors. Neuroreport 7, 2773–2776 (1996).

    CAS  PubMed  Google Scholar 

  89. 89

    Petralia, R. S., Wang, Y. X. & Wenthold, R. J. The NMDA receptor subunits NR2A and NR2B show histological and ultrastructural localization patterns similar to those of NR1. J. Neurosci. 14, 6102–6120 (1994).

    CAS  PubMed  Google Scholar 

  90. 90

    Huntley, G. W. et al. Distribution and synaptic localization of immunocytochemically identified NMDA receptor subunit proteins in sensory-motor and visual cortices of monkey and human. J. Neurosci. 14, 3603–3619 (1994).

    CAS  PubMed  Google Scholar 

  91. 91

    Johnson, R. R., Jiang, X. & Burkhalter, A. Regional and laminar differences in synaptic localization of NMDA receptor subunit NR1 splice variants in rat visual cortex and hippocampus. J. Comp. Neurol. 368, 335–355 (1996).

    CAS  PubMed  Google Scholar 

  92. 92

    Conti, F., Barbaresi, P., Melone, M. & Ducati, A. Neuronal and glial localization of NR1 and NR2A/B subunits of the NMDA receptor in the human cerebral cortex. Cereb. Cortex 9, 110–120 (1999).

    CAS  PubMed  Google Scholar 

  93. 93

    Baude, A., Nusser, Z., Molnar, E., McIlhinney, R. A. & Somogyi, P. High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus. Neuroscience 69, 1031–1055 (1995).

    CAS  PubMed  Google Scholar 

  94. 94

    Fujiyama, F. et al. Presynaptic localization of an AMPA-type glutamate receptor in corticostriatal and thalamostriatal axon terminals. Eur. J. Neurosci. 20, 3322–3330 (2004).

    PubMed  Google Scholar 

  95. 95

    Kharazia, V. N. & Weinberg, R. J. Immunogold localization of AMPA and NMDA receptors in somatic sensory cortex of albino rat. J. Comp. Neurol. 412, 292–302 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Matsubara, A., Laake, J. H., Davanger, S., Usami, S. & Ottersen, O. P. Organization of AMPA receptor subunits at a glutamate synapse: a quantitative immunogold analysis of hair cell synapses in the rat organ of Corti. J. Neurosci. 16, 4457–4467 (1996).

    CAS  PubMed  Google Scholar 

  97. 97

    Darstein, M., Petralia, R. S., Swanson, G. T., Wenthold, R. J. & Heinemann, S. F. Distribution of kainate receptor subunits at hippocampal mossy fiber synapses. J. Neurosci. 23, 8013–8019 (2003).

    CAS  Google Scholar 

  98. 98

    Kane-Jackson, R. & Smith, Y. Pre-synaptic kainate receptors in GABAergic and glutamatergic axon terminals in the monkey globus pallidus. Neuroscience 122, 285–289 (2003).

    CAS  PubMed  Google Scholar 

  99. 99

    Kieval, J. Z., Hubert, G. W., Charara, A., Pare, J. F. & Smith, Y. Subcellular and subsynaptic localization of presynaptic and postsynaptic kainate receptor subunits in the monkey striatum. J. Neurosci. 21, 8746–8757 (2001).

    CAS  PubMed  Google Scholar 

  100. 100

    Petralia, R., Wang, Y. & Wenthold, R. Histological and ultrastructural localization of the kainate receptor subunits, KA2 and GluR6/7, in the rat central nervous system using selective antipeptide antibodies. J. Comp. Neurol. 349, 85–110 (1994).

    CAS  Google Scholar 

  101. 101

    Pinheiro, P. S. et al. Presynaptic kainate receptors are localized close to release sites in rat hippocampal synapses. Neurochem. Int. 47, 309–316 (2005).

    CAS  PubMed  Google Scholar 

  102. 102

    Shigemoto, R. et al. Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J. Neurosci. 17, 7503–7522 (1997).

    CAS  PubMed  Google Scholar 

  103. 103

    Tamaru, Y., Nomura, S., Mizuno, N. & Shigemoto, R. Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience 106, 481–503 (2001).

    CAS  PubMed  Google Scholar 

  104. 104

    Dalezios, Y., Lujan, R., Shigemoto, R., Roberts, J. D. & Somogyi, P. Enrichment of mGluR7a in the presynaptic active zones of GABAergic and non-GABAergic terminals on interneurons in the rat somatosensory cortex. Cereb. Cortex 12, 961–974 (2002).

    PubMed  Google Scholar 

  105. 105

    Wada, E., Shigemoto, R., Kinoshita, A., Ohishi, H. & Mizuno, N. Metabotropic glutamate receptor subtypes in axon terminals of projection fibers from the main and accessory olfactory bulbs: a light and electron microscopic immunohistochemical study in the rat. J. Comp. Neurol. 393, 493–504 (1998).

    CAS  PubMed  Google Scholar 

  106. 106

    Shigemoto, R. et al. Target-cell-specific concentration of a metabotropic glutamate receptor in the presynaptic active zone. Nature 381, 523–525 (1996).

    CAS  Google Scholar 

  107. 107

    Ferraguti, F. et al. Metabotropic glutamate receptor 8-expressing nerve terminals target subsets of GABAergic neurons in the hippocampus. J. Neurosci. 25, 10520–10536 (2005).

    CAS  PubMed  Google Scholar 

  108. 108

    Scanziani, M., Gahwiler, B. H. & Charpak, S. Target cell-specific modulation of transmitter release at terminals from a single axon. Proc. Natl Acad. Sci. USA 95, 12004–12009 (1998).

    CAS  Google Scholar 

  109. 109

    Tzingounis, A. V. & Wadiche, J. I. Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nature Rev. Neurosci. 8, 935–947 (2007).

    CAS  Google Scholar 

  110. 110

    Oliet, S. H., Piet, R. & Poulain, D. A. Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science 292, 923–926 (2001).

    CAS  PubMed  Google Scholar 

  111. 111

    Piet, R., Vargova, L., Sykova, E., Poulain, D. A. & Oliet, S. H. Physiological contribution of the astrocytic environment of neurons to intersynaptic crosstalk. Proc. Natl Acad. Sci. USA 101, 2151–2155 (2004). This study showed that dynamic changes in the astrocytic coverage of magnocellular neurons during lactation alter the spillover of glutamate and modulate mGluR-mediated depression of GABAergic transmission.

    CAS  PubMed  Google Scholar 

  112. 112

    Losonczy, A., Somogyi, P. & Nusser, Z. Reduction of excitatory postsynaptic responses by persistently active metabotropic glutamate receptors in the hippocampus. J. Neurophysiol. 89, 1910–1919 (2003).

    CAS  PubMed  Google Scholar 

  113. 113

    Cao, C. Q., Tse, H. W., Jane, D. E., Evans, R. H. & Headley, P. M. Antagonism of mGlu receptors and potentiation of EPSCs at rat spinal motoneurones in vitro. Neuropharmacology 36, 313–318 (1997).

    CAS  PubMed  Google Scholar 

  114. 114

    Wang, L., Kitai, S. T. & Xiang, Z. Modulation of excitatory synaptic transmission by endogenous glutamate acting on presynaptic group II mGluRs in rat substantia nigra compacta. J. Neurosci. Res. 82, 778–787 (2005).

    CAS  PubMed  Google Scholar 

  115. 115

    Woodhall, G. L., Ayman, G. & Jones, R. S. Differential control of two forms of glutamate release by group III metabotropic glutamate receptors at rat entorhinal synapses. Neuroscience 148, 7–21 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Chen, H. X. & Roper, S. N. Tonic activity of metabotropic glutamate receptors is involved in developmental modification of short-term plasticity in the neocortex. J. Neurophysiol. 92, 838–844 (2004).

    CAS  PubMed  Google Scholar 

  117. 117

    Awatramani, G. B. & Slaughter, M. M. Intensity-dependent, rapid activation of presynaptic metabotropic glutamate receptors at a central synapse. J. Neurosci. 21, 741–749 (2001).

    CAS  PubMed  Google Scholar 

  118. 118

    Braga, M. F., Aroniadou-Anderjaska, V., Xie, J. & Li, H. Bidirectional modulation of GABA release by presynaptic glutamate receptor 5 kainate receptors in the basolateral amygdala. J. Neurosci. 23, 442–452 (2003).

    CAS  PubMed  Google Scholar 

  119. 119

    Xu, H. et al. Presynaptic regulation of the inhibitory transmission by GluR5-containing kainate receptors in spinal substantia gelatinosa. Mol. Pain 2, 29 (2006).

    PubMed  PubMed Central  Google Scholar 

  120. 120

    Herman, M. A. & Jahr, C. E. Extracellular glutamate concentration in hippocampal slice. J. Neurosci. 27, 9736–9741 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Zilberter, Y. Dendritic release of glutamate suppresses synaptic inhibition of pyramidal neurons in rat neocortex. J. Physiol. 528, 489–496 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Harkany, T. et al. Endocannabinoid-independent retrograde signaling at inhibitory synapses in layer 2/3 of neocortex: involvement of vesicular glutamate transporter 3. J. Neurosci. 24, 4978–4988 (2004).

    CAS  PubMed  Google Scholar 

  123. 123

    Levenes, C., Daniel, H. & Crepel, F. Retrograde modulation of transmitter release by postsynaptic subtype 1 metabotropic glutamate receptors in the rat cerebellum. J. Physiol. 537, 125–140 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Duguid, I. C., Pankratov, Y., Moss, G. W. & Smart, T. G. Somatodendritic release of glutamate regulates synaptic inhibition in cerebellar Purkinje cells via autocrine mGluR1 activation. J. Neurosci. 27, 12464–12474 (2007).

    CAS  PubMed  Google Scholar 

  125. 125

    Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).

    CAS  PubMed  Google Scholar 

  126. 126

    Halassa, M. M., Fellin, T. & Haydon, P. G. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol. Med. 13, 54–63 (2007).

    CAS  Google Scholar 

  127. 127

    Volterra, A. & Meldolesi, J. Astrocytes, from brain glue to communication elements: the revolution continues. Nature Rev. Neurosci. 6, 626–640 (2005).

    CAS  Google Scholar 

  128. 128

    Liu, Q. S., Xu, Q., Arcuino, G., Kang, J. & Nedergaard, M. Astrocyte-mediated activation of neuronal kainate receptors. Proc. Natl Acad. Sci. USA 101, 3172–3177 (2004).

    CAS  PubMed  Google Scholar 

  129. 129

    Liu, Q. S., Xu, Q., Kang, J. & Nedergaard, M. Astrocyte activation of presynaptic metabotropic glutamate receptors modulates hippocampal inhibitory synaptic transmission. Neuron Glia Biol. 1, 307–316 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Fiacco, T. A. & McCarthy, K. D. Intracellular astrocyte calcium waves in situ increase the frequency of spontaneous AMPA receptor currents in CA1 pyramidal neurons. J. Neurosci. 24, 722–732 (2004).

    CAS  PubMed  Google Scholar 

  131. 131

    Perea, G. & Araque, A. Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317, 1083–1086 (2007).

    CAS  Google Scholar 

  132. 132

    Cochilla, A. J. & Alford, S. Glutamate receptor-mediated synaptic excitation in axons of the lamprey. J. Physiol. 499, 443–457 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Cochilla, A. J. & Alford, S. NMDA receptor-mediated control of presynaptic calcium and neurotransmitter release. J. Neurosci. 19, 193–205 (1999).

    CAS  PubMed  Google Scholar 

  134. 134

    Schwartz, N. E. & Alford, S. Modulation of pre- and postsynaptic calcium dynamics by ionotropic glutamate receptors at a plastic synapse. J. Neurophysiol. 79, 2191–2203 (1998).

    CAS  PubMed  Google Scholar 

  135. 135

    Browning, K. N., Zheng, Z., Gettys, T. W. & Travagli, R. A. Vagal afferent control of opioidergic effects in rat brainstem circuits. J. Physiol. 575, 761–776 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Kamiya, H., Ozawa, S. & Manabe, T. Kainate receptor-dependent short-term plasticity of presynaptic Ca2+ influx at the hippocampal mossy fiber synapses. J. Neurosci. 22, 9237–9243 (2002).

    CAS  PubMed  Google Scholar 

  137. 137

    Geiger, J. R. & Jonas, P. Dynamic control of presynaptic Ca2+ inflow by fast-inactivating K+ channels in hippocampal mossy fiber boutons. Neuron 28, 927–939 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Lauri, S. E. et al. A role for Ca2+ stores in kainate receptor-dependent synaptic facilitation and LTP at mossy fiber synapses in the hippocampus. Neuron 39, 327–341 (2003).

    CAS  PubMed  Google Scholar 

  139. 139

    Awatramani, G. B., Price, G. D. & Trussell, L. O. Modulation of transmitter release by presynaptic resting potential and background calcium levels. Neuron 48, 109–121 (2005).

    CAS  PubMed  Google Scholar 

  140. 140

    Chavez, A. E., Singer, J. H. & Diamond, J. S. Fast neurotransmitter release triggered by Ca influx through AMPA-type glutamate receptors. Nature 443, 705–708 (2006). This study showed that the fast feedback inhibition at reciprocal synapses between A17 amacrine cells and rod bipolar cells in the retina is triggered by direct Ca2+ influx through AMPARs in a VGCC-independent manner.

    CAS  PubMed  Google Scholar 

  141. 141

    Breustedt, J. & Schmitz, D. Assessing the role of GLUK5 and GLUK6 at hippocampal mossy fiber synapses. J. Neurosci. 24, 10093–10098 (2004).

    CAS  PubMed  Google Scholar 

  142. 142

    Rodriguez-Moreno, A., Herreras, O. & Lerma, J. Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus. Neuron 19, 893–901 (1997).

    CAS  PubMed  Google Scholar 

  143. 143

    Rodriguez-Moreno, A. & Sihra, T. S. Kainate receptors with a metabotropic modus operandi. Trends Neurosci. 30, 630–637 (2007).

    CAS  PubMed  Google Scholar 

  144. 144

    Satake, S., Saitow, F., Rusakov, D. & Konishi, S. AMPA receptor-mediated presynaptic inhibition at cerebellar GABAergic synapses: a characterization of molecular mechanisms. Eur. J. Neurosci. 19, 2464–2474 (2004).

    PubMed  PubMed Central  Google Scholar 

  145. 145

    Casado, M., Dieudonne, S. & Ascher, P. Presynaptic N-methyl-D-aspartate receptors at the parallel fiber-Purkinje cell synapse. Proc. Natl Acad. Sci. USA 97, 11593–11597 (2000).

    CAS  PubMed  Google Scholar 

  146. 146

    O'Connor, V. et al. Calmodulin dependence of presynaptic metabotropic glutamate receptor signaling. Science 286, 1180–1184 (1999).

    CAS  PubMed  Google Scholar 

  147. 147

    Perroy, J. et al. Selective blockade of P/Q-type calcium channels by the metabotropic glutamate receptor type 7 involves a phospholipase C pathway in neurons. J. Neurosci. 20, 7896–7904 (2000).

    CAS  PubMed  Google Scholar 

  148. 148

    Huang, C. L., Feng, S. & Hilgemann, D. W. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ. Nature 391, 803–806 (1998).

    CAS  Google Scholar 

  149. 149

    Blackmer, T. et al. G protein βγ subunit-mediated presynaptic inhibition: regulation of exocytotic fusion downstream of Ca2+ entry. Science 292, 293–297 (2001).

    CAS  PubMed  Google Scholar 

  150. 150

    Blackmer, T. et al. G protein βγ directly regulates SNARE protein fusion machinery for secretory granule exocytosis. Nature Neurosci. 8, 421–425 (2005).

    CAS  PubMed  Google Scholar 

  151. 151

    Gerachshenko, T. et al. Gβγ acts at the C terminus of SNAP-25 to mediate presynaptic inhibition. Nature Neurosci. 8, 597–605 (2005).

    CAS  PubMed  Google Scholar 

  152. 152

    Delaney, A. J., Crane, J. W. & Sah, P. Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism. Neuron 56, 880–892 (2007).

    CAS  PubMed  Google Scholar 

  153. 153

    Huang, C. C., Chen, Y. L., Liang, Y. C. & Hsu, K. S. Role for cAMP and protein phosphatase in the presynaptic expression of mouse hippocampal mossy fibre depotentiation. J. Physiol. 543, 767–778 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Nicholls, R. E. et al. mGluR2 acts through inhibitory Gα subunits to regulate transmission and long-term plasticity at hippocampal mossy fiber-CA3 synapses. Proc. Natl Acad. Sci. USA 103, 6380–6385 (2006).

    CAS  PubMed  Google Scholar 

  155. 155

    Patil, S. T. et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Med. 13, 1102–1107 (2007).

    CAS  PubMed  Google Scholar 

  156. 156

    Schoppa, N. E. & Urban, N. N. Dendritic processing within olfactory bulb circuits. Trends Neurosci. 26, 501–506 (2003).

    CAS  PubMed  Google Scholar 

  157. 157

    Salin, P. A., Lledo, P. M., Vincent, J. D. & Charpak, S. Dendritic glutamate autoreceptors modulate signal processing in rat mitral cells. J. Neurophysiol. 85, 1275–1282 (2001).

    CAS  PubMed  Google Scholar 

  158. 158

    Schoppa, N. E. & Westbrook, G. L. AMPA autoreceptors drive correlated spiking in olfactory bulb glomeruli. Nature Neurosci. 5, 1194–1202 (2002).

    CAS  PubMed  Google Scholar 

  159. 159

    Isaacson, J. S. & Strowbridge, B. W. Olfactory reciprocal synapses: dendritic signaling in the CNS. Neuron 20, 749–761 (1998).

    CAS  PubMed  Google Scholar 

  160. 160

    Schoppa, N. E., Kinzie, J. M., Sahara, Y., Segerson, T. P. & Westbrook, G. L. Dendrodendritic inhibition in the olfactory bulb is driven by NMDA receptors. J. Neurosci. 18, 6790–6802 (1998).

    CAS  PubMed  Google Scholar 

  161. 161

    Taniguchi, M. & Kaba, H. Properties of reciprocal synapses in the mouse accessory olfactory bulb. Neuroscience 108, 365–370 (2001).

    CAS  PubMed  Google Scholar 

  162. 162

    Chen, W. R., Xiong, W. & Shepherd, G. M. Analysis of relations between NMDA receptors and GABA release at olfactory bulb reciprocal synapses. Neuron 25, 625–633 (2000).

    CAS  PubMed  Google Scholar 

  163. 163

    Halabisky, B., Friedman, D., Radojicic, M. & Strowbridge, B. W. Calcium influx through NMDA receptors directly evokes GABA release in olfactory bulb granule cells. J. Neurosci. 20, 5124–5134 (2000).

    CAS  PubMed  Google Scholar 

  164. 164

    Higgins, G. A. et al. Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. Neuropharmacology 46, 907–917 (2004).

    CAS  PubMed  Google Scholar 

  165. 165

    Altinbilek, B. & Manahan-Vaughan, D. Antagonism of group III metabotropic glutamate receptors results in impairment of LTD but not LTP in the hippocampal CA1 region, and prevents long-term spatial memory. Eur. J. Neurosci. 26, 1166–1172 (2007).

    PubMed  Google Scholar 

  166. 166

    Callaerts-Vegh, Z. et al. Concomitant deficits in working memory and fear extinction are functionally dissociated from reduced anxiety in metabotropic glutamate receptor 7-deficient mice. J. Neurosci. 26, 6573–6582 (2006).

    CAS  PubMed  Google Scholar 

  167. 167

    Holscher, C. et al. Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory. Behav. Brain Res. 154, 473–481 (2004).

    CAS  PubMed  Google Scholar 

  168. 168

    Holscher, C. et al. Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory. Learn. Mem. 12, 450–455 (2005).

    PubMed  Google Scholar 

  169. 169

    Frotscher, M., Jonas, P. & Sloviter, R. S. Synapses formed by normal and abnormal hippocampal mossy fibers. Cell Tissue Res. 326, 361–367 (2006).

    PubMed  Google Scholar 

Download references


We thank D. Perrais, S. Sachidhanandam and C. Blanchet for critical reading of the manuscript. C.M. is supported by grants from the Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche (ANR grant “PreSynGlu”), the Conseil Régional d'Aquitaine, and the European Commission (contract LSH-2004-019055). P.P. was supported by Fundação para a Ciência e a Tecnologia (grant SFRH/BD/5319/2001).

Author information



Corresponding author

Correspondence to Christophe Mulle.

Related links

Related links


Christophe Mulle's homepage



Presynaptic receptors that are activated by neurotransmitters released from the same nerve terminals in which the receptors themselves are located.

Active zone

A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and neurotransmitter release.


Presynaptic receptors that are activated by neurotransmitters released from nerve terminals other than the one in which the receptors themselves are located.

Inhibitory postsynaptic currents

(IPSCs). Currents that are generated when GABA activates GABAA receptors.

Paired-pulse ratio

A measure of a presynaptic form of short-term plasticity that describes the ability of synapses to change neurotransmitter release on the second of two closely spaced afferent stimulations. It is thought to depend on residual Ca2+ in the presynaptic terminal.

Failure rate

The probability that a presynaptic action potential will fail to produce a postsynaptic response.

Spontaneous excitatory postsynaptic currents

(Spontaneous EPSCs). Currents that are generated by action-potential-dependent and -independent release of neurotransmitter in the absence of experimental electrical stimulation. In this Review, we consider EPSCs to be mediated by iGluRs.

Miniature excitatory postsynaptic currents

(Miniature EPSCs). Currents that are observed in the absence of presynaptic action potentials; they are thought to correspond to the response that is elicited by a single vesicle of transmitter.

Frequency facilitation

A form of short-term plasticity in which modest changes in stimulus frequencies cause a growth in synaptic responses.

Long-term potentiation

(LTP). A persistent strengthening of synaptic transmission in response to strong, correlated input.

Long-term depression

(LTD). The converse of LTP: in LTD there is a long-lasting and activity-dependent decrease in synaptic efficacy.


The phenomenon whereby a current flowing through a channel does not flow with the same ease from one side as from the other.

SNARE complex

(Soluble NSF attachment protein (SNAP)-receptor complex). A trimeric complex that is essential for neurotransmitter vesicle fusion with the cell membrane.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pinheiro, P., Mulle, C. Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat Rev Neurosci 9, 423–436 (2008).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing