Our results show that EGABA depolarization relies on Zn2+-mediated KCC2 functional impairment, disclosing the underlying mechanism: glioma-released glutamate activates neuronal GluRs, causing neuronal intracellular Zn2+ rise which, through Src/TrkB activation, reduces KCC2 activity, leading to intracellular [Cl−] increase and EGABA depolarization. Here, SLC12A5 is linked to glioma.