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bioRxiv · 10.1101/2025.03.09.642262

Modulation of microRNA-502-3p significantly influences synaptic activity, dendritic spine density and mitochondrial morphology in the mice brain

Sharma, B.·Rodarte, D.·Goyal, G.·Miranda, M.·Perez, R. A.·Montes, L.·Donepudi, K.·Eadha, S.·kumar, S.
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Abstract

Synapse dysfunction is the root cause of Alzheimers disease (AD). Uninterrupted and regulated synapse action is crucial to maintain healthy brain function. Our previous study discovered microRNA-502-3p (miR-502-3p), a synapse-specific miRNA, highly expressed at the AD synapses. Further, in vitro studies unveiled the biological relevance of miR-502-3p in modulating GABA receptor function, synaptic activity and mitochondrial morphology. Current study focuses to investigate the role of miR-502-3p in vivo using stereotaxic injection of miR-502-3p overexpression (OE) and suppression (sponge) lentivirus (LV) into the hippocampus of C57BL/6 wild-type (WT) mice. MiR-502-3p OE and sponge LV were characterized by transducing HT22 cells followed by QRT-PCR and miRNAScope analysis of miR-502-3p. MiR-502-3p OE LV showed a very high-fold upregulation and sponge LV showed significant reduction in miR-502-3p levels. MiR-502-3p OE and sponge LV were injected into three months old WT mice brain hippocampus. Overexpression and suppression effects of miR-502-3p were studied on synaptic proteins, synapse number, mitochondrial morphology and dendritic spine density at eight-weeks post-injection. Mice injected with miR-502-3p OE LV showed reduced levels of synaptic proteins, diminished synapse formation, defective mitochondrial morphology and reduced dendritic spine density relative to control LV treated mice. While mice treated with sponge LV showed elevated levels of synaptic proteins, augmented synapses, improved mitochondrial morphology and elongated dendrites and spine density. Our in vivo study unveiled translational abilities of miR-502-3p to restore synapse dysfunction in AD and other neurological disorders.

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Sharma, B., Rodarte, D., Goyal, G., Miranda, M., Perez, R. A., Montes, L., Donepudi, K., Eadha, S., kumar, S.. 2025-03-10. Modulation of microRNA-502-3p significantly influences synaptic activity, dendritic spine density and mitochondrial morphology in the mice brain. https://doi.org/10.1101/2025.03.09.642262

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