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.