Retroinhibition of presynaptic Ca2+ currents by endocannabinoids released via postsynaptic mGluR activation at a calyx synapse

Christopher Kushmerick, Gareth D. Price, Holger Taschenberger, Nagore Puente, Robert Renden, Jacques I. Wadiche, Robert Duvoisin, Pedro Grandes, Henrique Von Gersdorff

Research output: Contribution to journalArticle

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Abstract

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-damp 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-H-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.

Original languageEnglish (US)
Pages (from-to)5955-5965
Number of pages11
JournalJournal of Neuroscience
Volume24
Issue number26
DOIs
StatePublished - Jun 30 2004

Fingerprint

Endocannabinoids
Synapses
Cannabinoid Receptor CB1
Metabotropic Glutamate Receptors
Glutamic Acid
Cannabinoid Receptor Antagonists
AMPA Receptors
Exocytosis
N-Methyl-D-Aspartate Receptors
Action Potentials
Brain Stem
dihydroxyphenylethylene glycol
Electron Microscopy
Neurons
Light

Keywords

  • Calyx of Held
  • Cannabinoids
  • CB1 receptor
  • Exocytosis
  • Group I mGluRs
  • MNTB
  • Presynaptic Ca channels
  • Retrograde signaling

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Retroinhibition of presynaptic Ca2+ currents by endocannabinoids released via postsynaptic mGluR activation at a calyx synapse. / Kushmerick, Christopher; Price, Gareth D.; Taschenberger, Holger; Puente, Nagore; Renden, Robert; Wadiche, Jacques I.; Duvoisin, Robert; Grandes, Pedro; Von Gersdorff, Henrique.

In: Journal of Neuroscience, Vol. 24, No. 26, 30.06.2004, p. 5955-5965.

Research output: Contribution to journalArticle

Kushmerick, Christopher ; Price, Gareth D. ; Taschenberger, Holger ; Puente, Nagore ; Renden, Robert ; Wadiche, Jacques I. ; Duvoisin, Robert ; Grandes, Pedro ; Von Gersdorff, Henrique. / Retroinhibition of presynaptic Ca2+ currents by endocannabinoids released via postsynaptic mGluR activation at a calyx synapse. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 26. pp. 5955-5965.
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AU - Puente, Nagore

AU - Renden, Robert

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