Zinc Modulates Synaptic Transmission By Differentially Regulating Synaptic Glutamate Homeostasis In Hippocampus

A subset of presynaptic glutamatergic vesicles in the brain co-releases zinc (Zn2+) with glutamate into the synapse. However, the role of synaptically released Zn2+ is still under investigation. Here, we studied the effect of Zn2+ on glutamate homeostasis by measuring the evoked extracellular glutamate level (EGL) and the probability of evoked action potential (P-EAP) at the Zn2+-containing or zincergic mossy fiber-CA3 synapses of the rat hippocampus. We found that the application of Zn2+ (ZnCl2) exerted bidirectional effects on both EGL and P-EAP: facilitatory at low concentration (1 mu M) while repressive at high concentration (50 mu M). To determine the action of endogenous Zn2+, we also used extracellular Zn2+ chelator to remove the synaptically released Zn2+. Zn2+ chelation reduced both EGL and P-EAP, suggesting that endogenous Zn2+ 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 Zn2+ facilitated the release of glutamate. Moreover, a glutamate transporter was the molecular entity for the action of Zn2+ on glutamate uptake by which Zn2+ decreases glutamate availability. Taken together, we show a novel action of Zn2+, which is to biphasically regulate glutamate homeostasis via Zn2+ concentration-dependent synaptic facilitation and depression. Thus, co-released Zn2+ is physiologically important for enhancing weak stimulation, but potentially mitigates excessive stimulation to keep synaptic transmission within optimal physiological range.