Synaptic Zn²⁺ inhibits neurotransmitter release by promoting endocannabinoid synthesis

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.