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The Journal of Neuroscience, June 30, 2004, 24(26):5955-5965; doi:10.1523/JNEUROSCI.0768-04.2004

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Cellular/Molecular
Retroinhibition of Presynaptic Ca²⁺ Currents by Endocannabinoids Released via Postsynaptic mGluR Activation at a Calyx Synapse

Christopher Kushmerick,^1 * Gareth D. Price,^1 * Holger Taschenberger,² Nagore Puente,⁴ Robert Renden,¹ Jacques I. Wadiche,¹ Robert M. Duvoisin,³ Pedro Grandes,⁴ and Henrique von Gersdorff¹

¹The Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, ²Max Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany, ³The Neurological Sciences Institute, Oregon Health and Science University, Beaverton, Oregon 97006, and ⁴Department of Neurosciences, Faculty of Medicine and Dentistry, Basque Country University, 699-48080 Bilbao, Spain

We investigated the mechanisms by which activation of group I metabotropic glutamate receptors (mGluRs) and CB1 cannabinoid receptors (CB1Rs) leads to inhibition of synaptic currents at the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) of the rat auditory brainstem. In 50% of the MNTB neurons tested, activation of group I mGluRs by the specific agonist (s)-3,5-dihydroxyphenylglycine (DHPG) reversibly inhibited AMPA receptor- and NMDA receptor-mediated EPSCs to a similar extent and reduced paired-pulse depression, suggestive of an inhibition of glutamate release. Presynaptic voltage-clamp experiments revealed a reversible reduction of Ca²⁺ currents by DHPG, with no significant modification of the presynaptic action potential waveform. Likewise, in 50% of the tested cells, the CB1 receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN) reversibly inhibited EPSCs, presynaptic Ca²⁺ currents, and exocytosis. For a given cell, the amount of inhibition by DHPG correlated with that by WIN. Moreover, the inhibitory action of DHPG was blocked by the CB1R antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) and occluded by WIN, indicating that DHPG and WIN operate via a common pathway. The inhibition of EPSCs by DHPG, but not by WIN, was abolished after dialyzing 40 mM BAPTA into the postsynaptic cell, suggesting that DHPG activated postsynaptic mGluRs. Light and electron microscopy immunolabeling indicated a presynaptic expression of CB1Rs and postsynaptic localization of mGluR1a. Our data suggest that activation of postsynaptic mGluRs triggers the Ca²⁺-dependent release of endocannabinoids that activate CB1 receptors on the calyx terminal, which leads to a reduction of presynaptic Ca²⁺ current and glutamate release.

Key words: presynaptic Ca channels; CB1 receptor; cannabinoids; MNTB; calyx of Held; retrograde signaling; group I mGluRs; exocytosis

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Received Aug 17, 2003; revised May 12, 2004; accepted May 13, 2004.

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