Oxidative stress induced by brain ischemia upregulates transient receptor potential melastatin-like-7 (TRPM7) expression and currents, which could contribute to neurotoxicity and cell death. Accordingly, suppression of TRPM7 reduces neuronal death, tissue damage and motor deficits. However, the neuroprotective effects of TRPM7 suppression in different cell types have not been investigated. Here, we found that induction of ischemia resulted in loss of parvalbumin (PV) gamma-aminobutyric acid (GABAergic) neurons more than Ca²⁺/calmodulin-kinase II (CaMKII) glutamatergic neurons in the mouse cortex. Furthermore, brain ischemia increased TRPM7 expression in PV neurons more than that in CaMKII neurons. We generated two lines of conditional knockout mice of TRPM7 in GABAergic PV neurons (PV-TRPM7^-/-) and in glutamatergic neurons (CaMKII-TRPM7^-/-). Following exposure to brain ischemia, we found that deleting TRPM7 reduced the infarct volume in both lines of transgenic mice. However, the volume in PV-TRPM7^-/- mice was more significantly lower than that in the control group. Neuronal survival of both GABAergic and glutamatergic neurons was increased in PV-TRPM7^-/- mice; meanwhile, only glutamatergic neurons were protected in CaMKII-TRPM7^-/-. At the behavioral level, only PV-TRPM7^-/- mice exhibited significant reductions in neurological and motor deficits. Inflammatory mediators such as GFAP, Iba1 and TNF-α were suppressed in PV-TRPM7^-/- more than in CaMKII-TRPM7^-/-. Mechanistically, p53 and cleaved caspase-3 were reduced in both groups, but the reduction in PV-TRPM7^-/- mice was more than that in CaMKII-TRPM7^-/- following ischemia. Upstream from these signaling molecules, the Akt anti-oxidative stress signaling was activated only in PV-TRPM7^-/- mice. Therefore, deleting TRPM7 in GABAergic PV neurons might have stronger neuroprotective effects against ischemia pathologies than doing so in glutamatergic neurons.

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