Zinc modulates synaptic transmission by differentially regulating synaptic glutamate homeostasis in hippocampus.

A subset of presynaptic glutamatergic vesicles in the brain co-releases zinc (Zn ) with glutamate into the synapse. However, the role of synaptically released Zn is still under investigation. Here, we studied the effect of Zn on glutamate homeostasis by measuring the evoked extracellular glutamate level (EGL) and the probability of evoked action potential (P ) at the Zn -containing or zincergic mossy fiber-CA3 synapses of the rat hippocampus. We found that the application of Zn (ZnCl ) exerted bidirectional effects on both EGL and P : facilitatory at low concentration (1 µM) while repressive at high concentration (50 µM). To determine the action of endogenous Zn , we also used extracellular Zn chelator to remove the synaptically released Zn . Zn chelation reduced both EGL and P , suggesting that endogenous Zn has mainly a facilitative role in glutamate secretion on physiological condition. We revealed that calcium/calmodulin-dependent protein kinase II was integral to the mechanism by which Zn facilitated the release of glutamate. Moreover, a glutamate transporter was the molecular entity for the action of Zn on glutamate uptake by which Zn decreases glutamate availability. Taken together, we show a novel action of Zn , which is to biphasically regulate glutamate homeostasis via Zn concentration-dependent synaptic facilitation and depression. Thus, co-released Zn is physiologically important for enhancing weak stimulation, but potentially mitigates excessive stimulation to keep synaptic transmission within optimal physiological range.