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The Journal of Neurophysiology Vol. 85 No. 3 March 2001, pp. 1185-1196
Copyright ©2001 by the American Physiological Society
1Division of Neurology, Department of Pediatrics, University of Pennsylvania School of Medicine, the Pediatric Regional Epilepsy Program of the Children's Hospital of Philadelphia, and the Joseph Stokes Jr. Research Institute of Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4318; and 2Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0599
Lin, Dean D.,
Akiva S. Cohen, and
Douglas
A. Coulter.
Zinc-Induced Augmentation of Excitatory Synaptic Currents and
Glutamate Receptor Responses in Hippocampal CA3 Neurons. J. Neurophysiol. 85: 1185-1196, 2001. Zinc is
found throughout the CNS at synapses co-localized with glutamate in
presynaptic terminals. In particular, dentate granule cells' (DGC)
mossy fiber (MF) axons contain especially high concentrations of zinc
co-localized with glutamate within vesicles. To study possible
physiological roles of zinc, visualized slice-patch techniques were
used to voltage-clamp rat CA3 pyramidal neurons, and miniature
excitatory postsynaptic currents (mEPSCs) were isolated. Bath-applied
zinc (200 µM) enhanced median mEPSC peak amplitudes to 153.0% of
controls, without affecting mEPSC kinetics. To characterize this
augmentation further, rapid agonist application was performed on
perisomatic outside-out patches to coapply zinc with glutamate
extremely rapidly for brief (1 ms) durations, thereby emulating release
kinetics of these substances at excitatory synapses. When zinc was
coapplied with glutamate, zinc augmented peak glutamate currents
(mean ± SE, 116.6 ± 2.8% and 143.8 ± 9.8%
of controls at 50 and 200 µM zinc, respectively). This zinc-induced
potentiation was concentration dependent, and pharmacological isolation
of 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptor-mediated currents (AMPAR currents) gave results similar to
those observed with glutamate application (mean, 115.0 ± 5.4%
and 132.5 ± 9.1% of controls at 50 and 200 µM zinc,
respectively). Inclusion of the AMPAR desensitization blocker
cyclothiazide in the control solution, however, abolished zinc-induced
augmentation of glutamate-evoked currents, suggesting that zinc may
potentiate AMPAR currents by inhibiting AMPAR desensitization. Based on
the results of the present study, we hypothesize that zinc is a
powerful modulator of both excitatory synaptic transmission and
glutamate-evoked currents at physiologically relevant concentrations.
This modulatory role played by zinc may be a significant factor in
enhancing excitatory neurotransmission and could significantly regulate
function at the mossy fiber-CA3 synapse.
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