Synaptic Zn2+ inhibits neurotransmitter release by promoting endocannabinoid synthesis

Tamara Perez-Rosello, Charles T. Anderson, Francisco J. Schopfer, Yanjun Zhao, David Gilad, Sonia R. Salvatore, Bruce A. Freeman, Michal Hershfinkel, Elias Aizenman, Thanos Tzounopoulos

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


Although it is well established that many glutamatergic neurons sequester Zn2++ within their synaptic vesicles, the physiological significance of synaptic Zn2+ remains poorly understood. In experiments performed in a Zn2++-enriched auditory brainstem nucleus-the dorsal cochlear nucleus-we discovered that synaptic Zn2++ and GPR39, a putative metabotropic Zn2++-sensing receptor (mZnR), are necessary for triggering the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). The postsynaptic production of 2-AG, in turn, inhibits presynaptic probability of neurotransmitter release, thus shaping synaptic strength and short-term synaptic plasticity. Zn2++-induced inhibition of transmitter release is absent in mutant mice that lack either vesicular Zn2++ or the mZnR. Moreover, mass spectrometry measurements of 2-AG levels reveal that Zn2++-mediated initiation of 2-AG synthesis is absent in mice lacking the mZnR. We reveal a previously unknown action of synaptic Zn2++: synaptic Zn2++ inhibits glutamate release by promoting 2-AG synthesis.

Original languageEnglish
Pages (from-to)9259-9272
Number of pages14
JournalJournal of Neuroscience
Issue number22
StatePublished - 29 May 2013

ASJC Scopus subject areas

  • General Neuroscience


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