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Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids

Abstract

Many types of neurons can release endocannabinoids that act as retrograde signals to inhibit neurotransmitter release from presynaptic terminals. Little is known, however, about the properties or role of such inhibition under physiological conditions. Here we report that brief bursts of presynaptic activity evoked endocannabinoid release, which strongly inhibited parallel fiber–to–Purkinje cell synapses in rat cerebellar slices. This retrograde inhibition was triggered by activation of either postsynaptic metabotropic or ionotropic glutamate receptors and was restricted to synapses activated with high-frequency bursts. Thus, endocannabinoids allow neurons to inhibit specific synaptic inputs in response to a burst, thereby dynamically fine-tuning the properties of synaptic integration.

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Figure 1: Brief trains of parallel fiber stimulation inhibit EPSPs in Purkinje cells by evoking endocannabinoid release.
Figure 2: Brief presynaptic bursts lead to reliable and reproducible endocannabinoid-mediated inhibition of presynaptic calcium entry.
Figure 3: The roles of mGluR1s, AMPA receptors and postsynaptic action potentials in the production of retrograde inhibition.
Figure 4: Both AMPA and metabotropic glutamate receptors can trigger endocannabinoid release under physiological conditions.
Figure 5: Presynaptic modulation by endocannabinoids is highly sensitive to both stimulation number and frequency.
Figure 6: Endocannabinoid modulation is synapse-specific.
Figure 7: Parallel fiber activation evokes localized postsynaptic responses.
Figure 8: Synapse specificity of the local signals triggering endocannabinoid release.

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Acknowledgements

We thank M. Beierlein, D. Blitz, K. Foster, A. Kreitzer, P. Safo and M. Xu-Friedman for comments on the manuscript. This work was supported by the US National Institutes of Health (RO1 NS 32405, RO1 NS 44396 and 5 T32 NS07484-02).

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Correspondence to Wade G Regehr.

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Brown, S., Brenowitz, S. & Regehr, W. Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids. Nat Neurosci 6, 1048–1057 (2003). https://doi.org/10.1038/nn1126

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