INTRODUCTION: The hippocampal region CA2 is exceptionally resistant to excitotoxic injury, unlike the adjacent, highly vulnerable CA1 area. Although this phenomenon is well documented, the molecular and cellular basis for such selective neuroprotection remains unclear. As calcium homeostasis differ between CA regions, and mitochondria are critical for calcium fluxes in neuronal stress, the between-region differences in mitochondrial calcium uptake may contribute to regional differences in vulnerability.

AIM(S): We aimed to determine whether the Mitochondrial Calcium Uniporter (MCU), recently identified as enriched in CA2 neurons, contributes to resistance against excitotoxicity.

METHOD(S): MCU distribution was examined using immunohistochemistry in rodent hippocampal sections. N-methyl-D-aspartate (NMDA)-exposed organotypic hippocampal slices were used as in vitro model of excitotoxicity. Region-specific changes in MCU expression and neuronal survival were studied in NMDA-exposed slices. MCU was pharmacologically inhibited using MCU-i4.

RESULTS: MCU expression was markedly higher in CA2 than in CA1, closely matching regional resistance to excitotoxicity. NMDA exposure increased MCU levels specifically in CA2. MCU inhibition sensitized intrinsically resistant CA2 neurons to NMDA-induced damage in a dose-dependent manner, while CA1 neurons, with low MCU expression, were only minimally affected.

CONCLUSIONS: Our findings show that CA2 neurons are protected against excitotoxic injury by MCU, suggesting a unique mitochondrial calcium handling in these cells. This finding highlights a context-dependent role of MCU in neuronal survival and reveals mechanisms underlying CA2's intrinsic resistance to excitotoxic stress.

FINANCIAL SUPPORT: National Science Centre, Poland (2023/51/B/NZ4/02605, 2023/49/N/NZ4/02660, 2017/26/E/NZ3/01144. (J.G.-B)) and Mossakowski Medical Research Institute, Polish Academy of Sciences (Internal Fund no. 24).