Extracellular Vesicles in the Forebrain Display Reduced miR-346 and miR-331-3p in a Rat Model of Chronic Temporal Lobe Epilepsy.
Epilepsy
Epileptogenesis
Exosomes
Extracellular vesicles
MicroRNAs
Seizures
Temporal lobe epilepsy
mTOR signaling pathway
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Mar 2020
Mar 2020
Historique:
received:
19
07
2019
accepted:
22
09
2019
pubmed:
10
12
2019
medline:
15
12
2020
entrez:
9
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31813125
doi: 10.1007/s12035-019-01797-1
pii: 10.1007/s12035-019-01797-1
pmc: PMC8011947
mid: NIHMS1546031
doi:
Substances chimiques
MicroRNAs
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1674-1687Subventions
Organisme : Texas Emerging Technology Fund
ID : No number
Organisme : BLRD VA
ID : I01 BX000883
Pays : United States
Organisme : U.S. Department of Defense
ID : W81XWH-14-1-0558
Organisme : U.S. Department of Veterans Affairs
ID : I01BX000883
Organisme : NINDS NIH HHS
ID : R01 NS106907
Pays : United States
Organisme : BLRD VA
ID : IK6 BX003612
Pays : United States
Organisme : BLRD VA
ID : I01 BX002351
Pays : United States
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