Synaptic activation of kainate receptors gates presynaptic CB1 signaling at GABAergic synapses

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Abstract

Glutamate can control inhibitory synaptic transmission through activation of presynaptic kainate receptors. We found that glutamate released by train stimulation of Schaffer collaterals could lead to either short-term depression or short-term facilitation of inhibitory synaptic transmission in mouse CA1 pyramidal neurons, depending on the presence of cannabinoid type 1 (CB1) receptors on GABAergic afferents. The train-induced depression of inhibition (t-Di) required the mobilization of 2-arachidonoylglycerol through postsynaptic activation of metabotropic glutamate receptors and [Ca2+] rise. GluK1 (GluR5)-dependent depolarization of GABAergic terminals enabled t-Di by facilitating presynaptic CB1 signaling. Thus, concerted activation of presynaptic CB1 receptors and kainate receptors mediates short-term depression of inhibitory synaptic transmission. In contrast, in inhibitory connections expressing GluK1, but not CB1, receptors, train stimulation of Schaffer collaterals led to short-term facilitation. Thus, activation of kainate receptors by synaptically released glutamate gates presynaptic CB1 signaling, which in turn controls the direction of short-term heterosynaptic plasticity.

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Figure 1: GluK1-KARs mediate t-Di.
Figure 2: CB1 receptors are required for the expression of t-Di.
Figure 3: t-Di requires postsynaptic mobilization of 2-AG.
Figure 4: GluK1 KAR–dependent depolarization enhances the efficacy of CB1 signaling.
Figure 5: t-Di is present in unitary connections expressing CB1 receptors.
Figure 6: In the absence of ECS signaling, GluK1 KARs facilitate inhibitory transmission.

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Acknowledgements

We thank the members of the laboratories of G. Marsicano and C. Mulle for fruitful discussions, P. Pinheiro for help during the experiments and A. Vimeney, D. Gonzales and the Genotyping Facility of the NeuroCentre Magendie for mouse genotyping. We are grateful to K. Mackie (Indiana University) for providing the CB1 antiserum. We thank J.P. Mazat, D. Commenges, C. Schwierz and L. Rosinus for help with statistical analyses. We thank K. Nave, J. Rubenstein, M. Ekker and G. Schütz for the use of Cre-expressing mouse lines. We also thank F. Chaouloff and N. Rebola for comments on the manuscript. This work was supported by an AVENIR grant of the Institut National de la Santé et de la Recherche Médicale (INSERM) in partnership with the Foundation Bettencourt-Schueller (G.M.), by the Agence National de la Recherche (ANR-06-NEUR-043-01 to G.M. and ANR-05-NEUR-033-01 to C.M.), by the Conseil Régional d'Aquitaine (G.M. and C.M.), by the Fundação para a Ciência e a Tecnologia, Portugal (J.L.), the Centre National de la Recherche Scientifique (C.M.) and European Commission Coordination Action Network of European Neuroscience Institutes (ENINET) (LSHM-CT-2005-19063 to G.M.).

Author information

J.L. conducted the electrophysiological experiments, A.C. carried out the anatomical studies, M.C. performed the glutamate uncaging experiments and F.C. carried out the biochemical assays. J.L., C.M. and G.M. designed the experiments and wrote the manuscript.

Correspondence to Christophe Mulle.

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Lourenço, J., Cannich, A., Carta, M. et al. Synaptic activation of kainate receptors gates presynaptic CB1 signaling at GABAergic synapses. Nat Neurosci 13, 197–204 (2010) doi:10.1038/nn.2481

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