Abstract
Synaptic inhibition is a vital component in the control of cell excitability within the brain. Here we report a newly identified form of inhibitory synaptic plasticity, termed depolarization-induced potentiation of inhibition, in rodents. This mechanism strongly potentiated synaptic transmission from interneurons to Purkinje cells after the termination of depolarization-induced suppression of inhibition. It was triggered by an elevation of Ca2+ in Purkinje cells and the subsequent retrograde activation of presynaptic NMDA receptors. These glutamate receptors promoted the spontaneous release of Ca2+ from presynaptic ryanodine-sensitive Ca2+ stores. Thus, NMDA receptor–mediated facilitation of transmission at this synapse provides a regulatory mechanism that can dynamically alter the synaptic efficacy at inhibitory synapses.
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Acknowledgements
We thank A. Gibb, B. Clark, A. Hosie and P. Thomas for helpful discussions on the manuscript. This work was supported by the Biotechnology and Biological Sciences Research Council, Medical Research Council and GlaxoSmithKline. We thank S. Moss (University College London) for the NR1 antibody, P. Whiting (Merck, Sharp and Dohme) for the NR2 antibodies, D. Baker (Institute of Neurology, University College London) for SR141716A and T. Carter (National Institute for Medical Research) for the nitrophenyl-EGTA.
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Supplementary Fig. 1
Schematic diagram of the mechanism underlying DPI. The events that follow Purkinje cell depolarization leading to a rapid rise in postsynaptic cytosolic Ca2+ and the retrograde release of glutamate are depicted. The released glutamate activates presynaptic NMDA receptors present on basket/stellate cell axon terminals inducing a rise in bouton Ca2+ levels via NMDA receptors. This rise in Ca2+ facilitates CICR from presynaptic ryanodine-sensitive Ca2+ stores leading to a sustained increase in inhibitory synaptic transmission at the IN-PC synapse, termed DPI. (JPG 48 kb)
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Duguid, I., Smart, T. Retrograde activation of presynaptic NMDA receptors enhances GABA release at cerebellar interneuron–Purkinje cell synapses. Nat Neurosci 7, 525–533 (2004). https://doi.org/10.1038/nn1227
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DOI: https://doi.org/10.1038/nn1227
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