MAM-Mediated Mitochondrial Ca(2+) Overload and Endoplasmic Reticulum Stress Aggravates Synaptic Plasticity Impairment in Diabetic Mice.

Background: As a chronic threat to human and animal health, diabetes impairs cognition and synaptic plasticity through mechanisms that remain unresolved. This study aims to explore whether mitochondria-associated endoplasmic reticulum membrane (MAM)-mediated mitochondrial Ca(2+) overload and endoplasmic reticulum stress plays an important role in high-glucose-induced synaptic plasticity damage in hippocampal neurons. Methods and Results: In diabetic mice, cognitive dysfunction was tightly linked to the synaptic plasticity impairment, manifesting as significant reductions in both mRNA and protein levels of PSD-95, GAP-43, and SYP. Concomitantly, aberrant increases in MAM number and structural alterations, along with pronounced up-regulation of Mfn2, were observed in hippocampal tissue from diabetic mice and cultured hippocampal neurons exposed to high glucose. High glucose also elevated MAM-located Ca(2+) transporters (IP3R, GRP75, MCU, and VDAC1), provoking mitochondrial Ca(2+) overload and activating ERS, particularly via the IRE1α pathway. Knockdown of Mfn2 ameliorated these high-glucose-induced MAM abnormalities, suppressed mitochondrial Ca(2+) overload and ERS, and exerted a protective effect against high-glucose-induced synaptic plasticity damage. Application of the inhibitor MCU-i4 to block Ca(2+) transport within MAM reduced high-glucose-induced mitochondrial Ca(2+) overload, relieved ERS, and improved high-glucose-induced synaptic plasticity impairment. Application of the inhibitor 4μ8C to suppress the IRE1α pathway of ERS alleviated mitochondrial Ca(2+) overload and improved high-glucose-induced synaptic plasticity impairment. Conclusions: High glucose elicits MAM dysregulation, which precipitates reciprocal mitochondrial Ca(2+) overload and ER stress, jointly driving hippocampal synaptic plasticity impairment.