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Glutamate spillover suppresses inhibition by activating presynaptic mGluRs

Nature volume 404, pages 498–502 (2000)Cite this article

Abstract

Metabotropic glutamate receptors (mGluRs) found on synaptic terminals throughout the brain are thought to be important in modulating neurotransmission1,2. Activation of mGluRs by synaptically released glutamate depresses glutamate release from excitatory terminals3,4,5 but the physiological role of mGluRs on inhibitory terminals is unclear. We have investigated activation of mGluRs on inhibitory terminals within the cerebellar glomerulus, a structure in which GABA (γ-aminobutyric acid)-releasing inhibitory terminals and glutamatergic excitatory terminals are in close apposition and make axo-dendritic synapses onto granule cells6. Here we show that ‘spillover’ of glutamate, which is released from excitatory mossy fibres, inhibits GABA release from Golgi cell terminals by activating presynaptic mGluRs under physiological conditions. The magnitude of the depression of the inhibitory postsynaptic current is dependent on the frequency of mossy fibre stimulation, reaching 50% at 100 Hz. Furthermore, the duration of inhibitory postsynaptic current depression mirrors the time course of mossy fibre activity. Our results establish that mGluRs on inhibitory interneuron axons7 sense the activity of neighbouring excitatory synapses. This heterosynaptic mechanism is likely to boost the efficacy of active excitatory fibres by locally reducing the level of inhibition.

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Figure 1: Activation of presynaptic mGluRs depresses IPSCs in granule cells.
Figure 2: Mossy fibre stimulation depresses GABA release from Golgi cells in the absence of fast excitatory transmission.
Figure 3: Metabotrophic glutamate receptors mediate MFS-induced IPSC depression.
Figure 4: IPSC depression depends on duration and frequency of MFS.

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Acknowledgements

This work was supported by The Wellcome Trust, the European Union and the Medical Research Council (Research Studentship to S.J.M.). We thank A. Momiyama and T. Takahashi for helpful discussion, J. Clements for providing Axograph and D. Attwell, M. Farrant, M. Häusser, B. Katz and T. Takahashi for comments on the manuscript.

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  1. Department of Physiology, University College London, Gower Street, London, WC1E 6BT, UK

    Simon J. Mitchell & R. Angus Silver

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Correspondence to R. Angus Silver.

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Mitchell, S., Silver, R. Glutamate spillover suppresses inhibition by activating presynaptic mGluRs . Nature 404, 498–502 (2000). https://doi.org/10.1038/35006649

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