The astrocytic zinc transporter ZIP12 is a synaptic protein that contributes to synaptic zinc levels in mouse auditory cortex

Synaptically released zinc is a neuronal signaling system that arises from the actions of the presynaptic vesicular zinc transporter protein ZnT3. Mechanisms that regulate the actions of zinc at synapses are of great importance for many aspects of synaptic signaling in the brain. Here, we identify the astrocytic zinc transporter protein ZIP12 as a candidate mechanism that contributes to zinc clearance at cortical synapses. We identify small molecule compounds that antagonize the function of ZIP12 in heterologous expression systems, and we use one of these compounds, ZiMo12.8, to increase the concentration of ZnT3-dependent zinc at synapses in the brain of male and female mice to inhibit the activity of neuronal AMPA and NMDA glutamate receptors. These results identify a cellular mechanism and provide a pharmacological toolbox to target the molecular machinery that supports the actions of synaptic zinc in the brain.Significance Statement Synaptic zinc is loaded into presynaptic glutamatergic vesicles by the protein zinc transporter 3 (ZnT3), where it is co-released with glutamate during synaptic transmission. Evidence from clinical studies in humans shows that alterations in the expression of the neuronal zinc transporter protein ZnT3 and the astrocytic zinc transporter protein ZIP12 are associated with schizophrenia, suggesting that dysregulation of these brain-specific zinc transporter proteins may contribute altered synaptic signaling in the brain. Our results show that ZIP12 protein is expressed by astrocytes at synapses in the brain. We identify pharmacological agents that inhibit ZIP12 and we use them to modulate zinc levels in the brain. This research advances our understanding of the roles of synaptic zinc in health and disease.