Zinc transporter 3 (ZnT3) and vesicular zinc in central nervous system function

•ZnT3 is required for the activity-dependent release of zinc from neurons.•Zinc signaling affects many neurotransmitter receptors, and is generally inhibitory.•Zinc signaling modulates synaptic plasticity in several brain structures.•ZnT3 KO mice are broadly normal, both behaviourally and electrophysiologically.•However, behavioural abnormalities can be revealed by using rigorous tests.

Zinc transporter 3 (ZnT3) is the sole mechanism responsible for concentrating zinc ions within synaptic vesicles in a subset of the brain's glutamatergic neurons. This vesicular zinc can then be released into the synaptic cleft in an activity-dependent fashion, where it can exert many signaling functions. This review provides a comprehensive discussion of the localization and function of ZnT3 and vesicular zinc in the central nervous system. We begin by reviewing the fundamentals of zinc homeostasis and transport, and the discovery of ZnT3. We then focus on four main topics. I) The anatomy of the zincergic system, including its development and its modulation through experience-dependent plasticity. II) The role of zinc in intracellular signaling, with a focus on how zinc affects neurotransmitter receptors and synaptic plasticity. III) The behavioural characterization of the ZnT3 KO mouse, which lacks ZnT3 and, therefore, vesicular zinc. IV) The roles of ZnT3 and vesicular zinc in health and disease.