Mechanisms of zinc modulation of olfactory bulb AMPA receptors.

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors mediates most fast excitatory transmission. Glutamate binding to AMPA receptors (AMPARs) causes most AMPARs to rapidly and completely desensitize, and their desensitization kinetics influence synaptic timing. Thus, factors that alter AMPAR desensitization influence synaptic transmission. Synaptically released zinc is such a factor. Zinc is a neuromodulator with effects on amino acid receptors and synaptic transmission in many brain regions, including the olfactory bulb (OB). We have previously shown in the OB that zinc potentiates AMPAR-mediated currents at low concentrations (30 μM, 100 μM) and inhibits them at a higher concentration (1 mM). It has been hypothesized that zinc potentiates AMPARs by decreasing receptor desensitization. Here, we used cyclothiazide (CTZ), a drug that blocks AMPAR desensitization, to determine whether zinc-mediated potentiation and/or inhibition of AMPA-evoked currents reflect(s) changes in AMPAR desensitization. Zinc largely had biphasic concentration-dependent effects at OB AMPARs. CTZ completely blocked potentiation by zinc but had no significant effect on inhibition. There was a significant negative correlation between the degree of potentiation of AMPAR-mediated currents by 100 μM zinc and a quantitative measure of the degree of AMPAR desensitization (the steady-state to peak [S:P] ratio of AMPA-evoked currents), but no correlation between the degree of current inhibition by 1 mM zinc and the S:P ratio. Together, these findings suggest that low zinc concentrations potentiate rat OB AMPARs by decreasing receptor desensitization, but that the inhibitory effects of higher zinc concentrations are mediated by a separate mechanism.