State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
Cells. 2022 Mar 31;11(7):1178. doi: 10.3390/cells11071178.
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 Ca/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.
脑缺血引起的氧化应激上调瞬时受体电位 melastatin 样-7（TRPM7）的表达和电流，这可能导致神经毒性和细胞死亡。因此，抑制 TRPM7 可减少神经元死亡、组织损伤和运动功能障碍。然而，不同细胞类型中 TRPM7 抑制的神经保护作用尚未得到研究。在这里，我们发现诱导缺血导致小鼠皮层中的 parvalbumin（PV）γ-氨基丁酸（GABA 能）神经元比 Ca/calmodulin-kinase II（CaMKII）谷氨酸能神经元丢失更多。此外，脑缺血增加了 PV 神经元中 TRPM7 的表达，而不是 CaMKII 神经元。我们生成了两种条件性敲除小鼠，即 GABA 能 PV 神经元（PV-TRPM7）和谷氨酸能神经元（CaMKII-TRPM7）中的 TRPM7。暴露于脑缺血后，我们发现删除 TRPM7 可减少两种转基因小鼠的梗死体积。然而，PV-TRPM7 小鼠的体积明显低于对照组。PV-TRPM7 小鼠中 GABA 能和谷氨酸能神经元的存活率均增加；同时，只有 CaMKII-TRPM7 保护谷氨酸能神经元。在行为水平上，只有 PV-TRPM7 小鼠表现出明显的神经和运动功能障碍改善。GFAP、Iba1 和 TNF-α 等炎症介质在 PV-TRPM7 中的表达低于 CaMKII-TRPM7。在机制上，p53 和 cleaved caspase-3 在两组中均减少，但缺血后 PV-TRPM7 小鼠的减少量大于 CaMKII-TRPM7。在这些信号分子的上游，只有在 PV-TRPM7 小鼠中激活了 Akt 抗氧化应激信号。因此，在 GABA 能 PV 神经元中删除 TRPM7 可能比在谷氨酸能神经元中具有更强的抗缺血病理作用。
