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Zinc modulates synaptic transmission by differentially regulating synaptic glutamate homeostasis in hippocampus
Author(s) -
Shen Zhijun,
Haragopal Hariprakash,
Li Yang V.
Publication year - 2020
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.14749
Subject(s) - glutamate receptor , neurotransmission , glutamatergic , chemistry , synaptic cleft , synaptic vesicle , extracellular , neurotransmitter , metabotropic glutamate receptor , endogeny , homeostasis , biophysics , biochemistry , neuroscience , biology , microbiology and biotechnology , receptor , vesicle , membrane
A subset of presynaptic glutamatergic vesicles in the brain co‐releases zinc (Zn 2+ ) with glutamate into the synapse. However, the role of synaptically released Zn 2+ is still under investigation. Here, we studied the effect of Zn 2+ on glutamate homeostasis by measuring the evoked extracellular glutamate level (EGL) and the probability of evoked action potential ( P EAP ) at the Zn 2+ ‐containing or zincergic mossy fiber–CA3 synapses of the rat hippocampus. We found that the application of Zn 2+ (ZnCl 2 ) exerted bidirectional effects on both EGL and P EAP : facilitatory at low concentration (~1 µM) while repressive at high concentration (~50 µM). To determine the action of endogenous Zn 2+ , we also used extracellular Zn 2+ chelator to remove the synaptically released Zn 2+ . Zn 2+ chelation reduced both EGL and P EAP , suggesting that endogenous Zn 2+ 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 2+ facilitated the release of glutamate. Moreover, a glutamate transporter was the molecular entity for the action of Zn 2+ on glutamate uptake by which Zn 2+ decreases glutamate availability. Taken together, we show a novel action of Zn 2+ , which is to biphasically regulate glutamate homeostasis via Zn 2+ concentration‐dependent synaptic facilitation and depression. Thus, co‐released Zn 2+ is physiologically important for enhancing weak stimulation, but potentially mitigates excessive stimulation to keep synaptic transmission within optimal physiological range.