The divalent cation zinc is enriched in cerebral hemisphere and acts as a potent modulator of neuronal signaling (Marger et al., 2014). The vesicular transporter ZnT3 in certain glutamatergic neurons enables zinc co-release with glutamate. Synaptic source of zinc modulates multiple ion channels (e.g. inhibiting extra-synaptic NMDA receptors) (Marger et al., 2014). Surprisingly, we discovered that ZnT3 (Slc30a3) is highly and specifically expressed in SST/CR cells (Figure 6E), along with Zip1 (Slc39a1) and Zip7a (Slc39a7) transporters that uptake extracellular zinc into the cytosol. These results suggest that SST/CR cells co-release zinc and GABA. As most SST/CR cells are Martinotti cells that target the distal dendrites and spines of pyramidal neurons with abundant NMDARs (Silberberg and Markram, 2007), their powerful dendritic inhibition might be mediated through two parallel mechanisms: synaptic activation of GABAARs by GABA and extra-synaptic inhibition of NMDARs by zinc.
