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 theendocannabinoid 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.

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