Abstract
An initial precipitating injury in the brain, such as after status epilepticus (SE), evolves into chronic temporal lobe epilepsy (TLE). We investigated changes in the miRNA composition of extracellular vesicles (EVs) in the forebrain after the establishment of SE-induced chronic TLE. We induced SE in young Fischer 344 rats through graded intraperitoneal injections of kainic acid, which resulted in consistent spontaneous recurrent seizures at ~ 3 months post-SE. We isolated EVs from the entire forebrain of chronically epileptic rats and age-matched naïve control animals through an ultracentrifugation method and performed miRNA-sequencing studies to discern changes in the miRNA composition of forebrain-derived EVs in chronic epilepsy. EVs from both naïve and epileptic forebrains displayed spherical or cup-shaped morphology, a comparable size range, and CD63 expression but lacked the expression of a deep cellular marker GM130. However, miRNA-sequencing studies suggested downregulation of 3 miRNAs (miR-187-5p, miR-346, and miR-331-3p) and upregulation of 4 miRNAs (miR-490-5p, miR-376b-3p, miR-493-5p, and miR-124-5p) in EVs from epileptic forebrains with fold changes ranging from 1.5 to 2.4 (p < 0.0006; FDR < 0.05). By using geNorm and Normfinder software, we identified miR-487 and miR-221 as the best combination of reference genes for measurement of altered miRNAs found in the epileptic forebrain through qRT-PCR studies. The validation revealed that only miR-346 and miR-331-3p were significantly downregulated in EVs from the epileptic forebrain. The enrichment pathway analysis of these miRNAs showed an overrepresentation of signaling pathways that are linked to molecular mechanisms underlying chronic epilepsy, including GABA-ergic (miR-346 targets) and mTOR (miR-331-3p targets) systems. Thus, the packaging of two miRNAs into EVs in neural cells is considerably altered in chronic epilepsy. Functional studies on these two miRNAs may uncover their role in the pathophysiology and treatment of TLE.
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This work was supported by grants from the Department of Defense (W81XWH-14-1-0558 to A.K.S.), the State of Texas (Emerging Technology Fund to A.K.S.), and the Department of Veterans Affairs (Merit Award I01BX000883 and BLR&D Research Career Scientist award 1IK6BX003612 to A.K.S.). Daniel Gitai was supported by a Visiting Scientist Award from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Government of Brazil (D.L.G. Gitai).
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Conception: DLGG and AKS; research design: DLGG, RU, MK, and AKS; collection of data: DLGG, YDRS, RU, MK, and LNM; data analyses and interpretation: DLGG, YDRS, and AKS; preparation of figures: DLGG, YDRS, LNM, and AKS; manuscript writing: DLGG and AKS.
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The Animal Care and Use Committee of the Texas A&M University approved all animal experiments performed in this study.
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Gitaí, D.L.G., dos Santos, Y.D.R., Upadhya, R. et al. Extracellular Vesicles in the Forebrain Display Reduced miR-346 and miR-331-3p in a Rat Model of Chronic Temporal Lobe Epilepsy. Mol Neurobiol 57, 1674–1687 (2020). https://doi.org/10.1007/s12035-019-01797-1
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DOI: https://doi.org/10.1007/s12035-019-01797-1