Synaptically released zinc gates long-term potentiation in fear conditioning pathways

The functional role of releasable Zn2+ in the central nervous system remains unknown. Here we show that zinc transporter 3 (ZnT-3), which maintains a high concentration of Zn2+ in synaptic vesicles and serves as a marker for zinc-containing neurons, is enriched in the lateral nucleus of the amygdala and in the temporal area 3 of the auditory cortex, an area that conveys information about the auditory conditioned stimulus to the lateral nucleus of the amygdala, but not in other conditioned stimulus areas located in the auditory thalamus. Using whole-cell recordings from am amygdala slices, we demonstrated that activity-dependent release of chelatable Zn2+ is required for the induction of spike timing-dependent long-term potentiation in cortical input to the amygdala implicated in fear learning. Our data indicate that synaptically released Zn2+ enables long-term potentiation at the cortico-amygdala synapses by depressing feed-forward GABAergic inhibition of principal neurons. This regulatory mechanism, implicating pathway-dependent release of Zr2+, may serve an essential control function in assuring spatial specificity of long-lasting synaptic modifications in the neural circuit of a learned behavior.