RT Journal Article SR Electronic T1 Synaptic Zn2+ Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 9259 OP 9272 DO 10.1523/JNEUROSCI.0237-13.2013 VO 33 IS 22 A1 Tamara Perez-Rosello A1 Charles T. Anderson A1 Francisco J. Schopfer A1 Yanjun Zhao A1 David Gilad A1 Sonia R. Salvatore A1 Bruce A. Freeman A1 Michal Hershfinkel A1 Elias Aizenman A1 Thanos Tzounopoulos YR 2013 UL http://www.jneurosci.org/content/33/22/9259.abstract AB 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.