GABAB receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses

Abstract

Metabotropic γ-aminobutyric acid type B (GABAB) and glutamate receptors (mGluRs) are postsynaptically co-expressed at cerebellar parallel fiber (PF)–Purkinje cell (PC) excitatory synapses, but their functional interactions are unclear. We found that mGluR1 agonist-induced currents and [Ca2+]i increases in PCs were enhanced following co-activation of GABAB receptors. A GABAB antagonist and a G-protein uncoupler suppressed these effects. Low-concentration baclofen, a GABAB agonist, augmented mGluR1-mediated excitatory synaptic current produced by stimulating PFs. These results indicate that postsynaptic GABAB receptors functionally interact with mGluR1 and enhance mGluR1-mediated excitatory transmission at PF–PC synapses. The interaction between the two types of metabotropic receptors provides a likely mechanism for regulating cerebellar synaptic plasticity.

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Figure 1: Enhancement of 1S,3R-ACPD-induced inward current by GABA.
Figure 2: Selective enhancement of mGluR1-mediated current following GABABR activation.
Figure 3: Blockade of baclofen-induced enhancement of the mGluR1-mediated current response by the GABABR antagonist CGP62349.
Figure 4: Voltage-independent facilitation of GABABR-mediated enhancement of the 1S,3R-ACPD-induced currents, and comparisons of presynaptic and postsynaptic actions induced by baclofen.
Figure 5: Simultaneous recordings of GABABR activation-mediated enhancement of 1S,3R-ACPD-induced current and [Ca2+]i transients in a PC.
Figure 6: Effects of signal transduction modulators on the GABABR-induced enhancement of the mGluR1-mediated current.
Figure 7: Enhancement by baclofen of mGluR1-mediated slow EPSCs produced in response to PF stimulation.
Figure 8: Dose dependency of baclofen-induced enhancement and inhibition of mGluR1-mediated slow EPSCs, and the effects of synaptic GABABR activation on fast and slow EPSCs tested by using the GABABR antagonist CGP62349.

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Acknowledgements

We thank J. Bockaert, T. Murakoshi, D. Rusakov, F. Saitow and K. Yoshioka for comments on the manuscript and Novartis Pharma (Basel, Switzerland) for the gift of CGP62349. This work was supported in part by a Grant-in-Aid 0727910 (T.Y.) from the Ministry of Education, Science, Sports and Culture of Japan, and Grant-in-Aids 96L00310 (T.Y.) and 12780603 (M.H.) from the Japan Society for Promotion of Science. S.K. is a research director of CREST, JST (Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation).

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Correspondence to Shiro Konishi.

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Hirono, M., Yoshioka, T. & Konishi, S. GABAB receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses. Nat Neurosci 4, 1207–1216 (2001). https://doi.org/10.1038/nn764

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