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

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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.

Graphical Abstract

Schematic presentation depicts that Mdivi-1 rescues memory decline in scopolamine-induced amnesic male mice by ameliorating mitochondrial dynamics and hippocampal plasticity

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Data Availability

The data that support the findings of this study are available on the request from the corresponding author.

Abbreviations

AD:

Alzheimer’s disease

ANOVA:

Analysis of variance

ATP:

Adenosine triphosphate

cDNA:

Complementary DNA

CNS:

Central nervous system

Cyt-c:

Cytochrome-c

Drp1:

Dynamin-related protein 1

EDTA:

Ethylenediaminetetraacetic acid

Fis1:

Mitochondrial fission 1 protein

H2O2 :

Hydrogen peroxide

HRP:

Horseradish peroxidase

LTP:

Long-term potentiation

M:

Mitochondria

Mdivi-1:

Mitochondrial division inhibitor-1

Mfn:

Mitofusin

MMP:

Mitochondrial membrane potential

NOR:

Novel object recognition

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

PD:

Parkinson’s disease

PMSF:

Phenylmethanesulfonyl fluoride

RDV:

Relative density value

ROS:

Reactive oxygen species

SC:

Scopolamine

SEM:

Standard error of the mean

SOD:

Superoxide dismutase

TEM:

Transmission electron microscope

Tris:

2-Amino-2-(hydroxymethyl) propane-1,3,-diol

qRT-PCR:

Quantitative real-time PCR

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Acknowledgements

We are thankful to the Interdisciplinary School of Life Sciences (ISLS), BHU, for the Vibratome, Cryostat, qRT-PCR, and fluorescence microscopy facilities. We are also thankful to the TEM facility of Dr. Harisingh Gour Central University, Sagar, MP, India.

Funding

We acknowledge the Council of Scientific & Industrial Research (CSIR) for the Junior and Senior Research Fellowship and Indian Council of Medical Research (ICMR), New Delhi, for Senior Research Fellowship to EM, research grants from ICMR (5/4–5/153/Neuro/2015-NCD-I), Department of Science & Technology (EMR/2015/002178), Government of India, and National Academy of Sciences, India-Senior Scientist fellowship (NASI-303/12/2021) to MKT.

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Authors and Affiliations

  1. Biochemistry and Molecular Biology Laboratory, Centre of Advanced Study, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India

    Ela Mishra & Mahendra Kumar Thakur

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  1. Ela Mishra
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  2. Mahendra Kumar Thakur
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Contributions

EM: Conceptualization, Data curation, Formal Analysis, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review & editing; MKT: Conceptualization, Funding acquisition, Investigation, Project administration, Resources, Supervision, Validation, Writing – final review & editing.

Corresponding author

Correspondence to Mahendra Kumar Thakur.

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Ethical Approval

The current study was approved by the Institutional Animal Ethical Committee (IAEC Approval Reference No. BHU/DoZ/IAEC/2018–19/043), and experimentation was carried out by following CPCSEA guidelines.

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The authors declare no competing interests.

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Key Message

• Mdivi-1 enhances recognition and spatial memory of amnesic mice.

• Mdivi-1 alters mitochondrial dynamics-related proteins and promotes mitochondrial health.

• Mdivi-1 improves mitochondrial function by altering SOD, Catalase, ROS, and ATP.

• Mdivi-1 enhances myelination and attenuates neurodegeneration in amnesic mice.

• Mdivi-1 augments the dendritic arborization, spine density, and hippocampal plasticity.

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Mishra, E., Thakur, M.K. Mdivi-1 Rescues Memory Decline in Scopolamine-Induced Amnesic Male Mice by Ameliorating Mitochondrial Dynamics and Hippocampal Plasticity. Mol Neurobiol 60, 5426–5449 (2023). https://doi.org/10.1007/s12035-023-03397-6

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  • DOI: https://doi.org/10.1007/s12035-023-03397-6

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