Zinc-induced augmentation of excitatory synaptic currents and glutamate receptor responses in hippocampal CA3 neurons

Zinc is found throughout the CNS at synapses co-localized with glutamate in presynaptic terminals. In particular, dentate granule cells' (DGC) mossy f iber (MF) axons contain especially high concentrations of zinc co-localized with glutamate within vesicles. To study possible physiological roles of z inc, visualized slice-patch techniques were used to voltage-clamp rat CA3 p yramidal neurons, and miniature excitatory postsynaptic currents (mEPSCs) w ere isolated. Bath-applied zinc (200 muM) enhanced median mEPSC peak amplit udes to 153.0% of controls, without affecting mEPSC kinetics. To characteri ze this augmentation further, rapid agonist application was performed on pe risomatic outside-out patches to coapply zinc with glutamate extremely rapi dly 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 14 3.8 +/- 9.8% of controls at 50 and 200 muM zinc, respectively). This zinc-i nduced potentiation was concentration dependent, and pharmacological isolat ion of alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) rec eptor-mediated currents (AMPAR currents) gave results similar to those obse rved with glutamate application (mean, 115.0 +/- 5.4% and 132.5 +/- 9.1% of controls at 50 and 200 muM zinc, respectively). Inclusion of the AMPAR des ensitization blocker cyclothiazide in the control solution, however, abolis hed zinc-induced augmentation of glutamate-evoked currents, suggesting that zinc may potentiate AMPAR currents by inhibiting AMPAR desensitization. Ba sed on the results of the present study, we hypothesize that zinc is a powe rful modulator of both excitatory synaptic transmission and glutamate-evoke d currents at physiologically relevant concentrations. This modulatory role played by zinc may be a significant factor in enhancing excitatory neurotr ansmission and could significantly regulate function at the mossy fiber-CA3 synapse.