The bright side of mitochondrial calcium uniporter: MCU can protect hippocampal CA2 neurons from excitotoxic damage

Mitochondrial calcium uniporter (MCU) is a protein that facilitates calcium ion influx into mitochondria. It is well established that MCU, through mitochondrial Ca2+ overload, may promote neuronal death in different neuropathological conditions, especially those involving excitotoxicity. Surprisingly, MCU distribution in hippocampus is inversely proportional to susceptibility of individual hippocampal subregions to death – the highest MCU expression is found in CA2, the lowest - in CA1 (the most and the least resistant regions, respectively). The aim of my study was therefore to assess cell type-specific involvement of MCU in protection against excitotoxicity in hippocampus. Hippocampal rat organotypic slice cultures were used as a model for functional analyses. Excitotoxicity was induced using N-Methyl-D-aspartic acid (NMDA), and MCU was blocked with MCU-i4 inhibitor. Cell damage was estimated with propidium iodide. Distribution of MCU in organotypic cultures and in tissue was studied using immunohistochemistry. Exposure of hippocampal organotypic slices to NMDA induced region-dependent neuronal damage – strong in CA1 and minimal in CA2. Treatment with MCU-i4 alone didn’t affect neuronal survival in any region, but resulted in concentration-dependent sensitization of CA2 neurons to NMDA. Moreover, NMDA caused region-specific changes in MCU, namely - increase in MCU expression in CA2 and decrease in CA3. The obtained results demonstrate that MCU may support the resistance of CA2 neurons to excitotoxicity. These data establish a link between known phenotypes of this region and show that, in excitotoxicity, MCU doesn’t always mediate pathology, but, in specific populations of cells, it may exhibit neuroprotective properties.