The Astrocytic Zinc Transporter ZIP12 Is a Synaptic Protein That Contributes to Synaptic Zinc Levels in the Mouse Auditory Cortex

J Neurosci. 2025 Mar 26;45(13):e2067242025. doi: 10.1523/JNEUROSCI.2067-24.2025.

Abstract

Synaptically released zinc is a neuronal signaling system that arises from the actions of the presynaptic vesicular zinc transporter protein zinc transporter 3 (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, ZIP12 modulator 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.

Keywords: Slc30a3; Slc39a12; astrocytes; auditory cortex; synapses; zinc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes* / drug effects
  • Astrocytes* / metabolism
  • Auditory Cortex* / cytology
  • Auditory Cortex* / metabolism
  • Cation Transport Proteins* / antagonists & inhibitors
  • Cation Transport Proteins* / genetics
  • Cation Transport Proteins* / metabolism
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Synapses* / drug effects
  • Synapses* / metabolism
  • Zinc* / metabolism

Substances

  • Zinc
  • Cation Transport Proteins
  • Slc30a3 protein, mouse