Mdivi-1 Rescues Memory Decline in Scopolamine-Induced Amnesic Male Mice by Ameliorating Mitochondrial Dynamics and Hippocampal Plasticity

Abstract

Memory loss, often known as amnesia, is common in the elderly population and refers to forgetting facts and experiences. It is associated with increased mitochondrial fragmentation, though the contribution of mitochondrial dynamics in amnesia is poorly understood. Therefore, the present study is aimed at elucidating the role of Mdivi-1 in mitochondrial dynamics, hippocampal plasticity, and memory during scopolamine (SC)-induced amnesia. The findings imply that Mdivi-1 significantly increased the expression of Arc and BDNF proteins in the hippocampus of SC-induced amnesic mice, validating improved recognition and spatial memory. Moreover, an improved mitochondrial ultrastructure was attributed to a decline in the percentage of fragmented and spherical-shaped mitochondria after Mdivi-1 treatment in SC-induced mice. The significant downregulation of p-Drp1 (S616) protein and upregulation of Mfn2, LC3BI, and LC3BII proteins in Mdivi-1-treated SC-induced mice indicated a decline in fragmented mitochondrial number and healthy mitochondrial dynamics. Mdivi-1 treatment alleviated ROS production and Caspase-3 activity and elevated mitochondrial membrane potential, Vdac1 expression, ATP production, and myelination, resulting in reduced neurodegeneration in SC mice. Furthermore, the decline of pro-apoptotic protein cytochrome-c and increase of anti-apoptotic proteins Procaspase-9 and Bcl-2 in Mdivi-1-treated SC-induced mice suggested improved neuronal health. Mdivi-1 also increased the dendritic arborization and spine density, which was further corroborated by increased expression of synaptophysin and PSD95. In conclusion, the current study suggests that Mdivi-1 treatment improves mitochondrial ultrastructure and function through the regulation of mitochondrial dynamics. These changes further improve neuronal cell density, myelination, dendritic arborization, and spine density, decrease neurodegeneration, and improve recognition and spatial memory. Schematic presentation depicts that Mdivi-1 rescues memory decline in scopolamine-induced amnesic male mice by ameliorating mitochondrial dynamics and hippocampal plasticity.

Keywords: Amnesia; Hippocampus; Mdivi-1; Mitochondrial dynamics; Mitochondrial dysfunction; Neurodegeneration.