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.

Abstract

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.

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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.

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Acknowledgements

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).

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Glossary

Autoreceptors

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.

Heteroreceptors

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.

Rectification

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.

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Pinheiro, P., Mulle, C. Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat Rev Neurosci 9, 423–436 (2008). https://doi.org/10.1038/nrn2379

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