Altered Biogenesis and MicroRNA Content of Hippocampal Exosomes Following Experimental Status Epilepticus

Abstract

Repetitive or prolonged seizures (status epilepticus) can damage neurons within the hippocampus, trigger gliosis, and generate an enduring state of hyperexcitability. Recent studies have suggested that microvesicles including exosomes are released from brain cells following stimulation and tissue injury, conveying contents between cells including microRNAs (miRNAs). Here, we characterized the effects of experimental status epilepticus on the expression of exosome biosynthesis components and analyzed miRNA content in exosome-enriched fractions. Status epilepticus induced by unilateral intra-amygdala kainic acid in mice resulted in acute subfield-specific, bidirectional changes in hippocampal transcripts associated with exosome biosynthesis including up-regulation of endosomal sorting complexes required for transport (ESCRT)dependent and-independent pathways. Increased expression of exosome components including Alix were detectable in samples obtained 2 weeks after status epilepticus and changes occurred in both the ipsilateral and contralateral hippocampus. RNA sequencing of exosome-enriched fractions prepared using two different techniques detected a rich diversity of conserved miRNAs and showed that status epilepticus selectively alters miRNA contents. We also characterized editing sites of the exosomeenriched miRNAs and found six exosome-enriched miRNAs that were adenosine-toinosine (ADAR) edited with the majority of the editing events predicted to occur within miRNA seed regions. However, the prevalence of these editing events was not altered by status epilepticus. These studies demonstrate that status epilepticus alters the exosome pathway and its miRNA content, but not editing patterns. Further functional studies will be needed to determine if these changes have pathophysiological significance for epileptogenesis.

Circulating Exosome microRNAs as Diagnostic Biomarkers of Dementia

“…These contents provide copious amounts of biological information that can potentially reveal information about disease status at multiple levels (Koritzinsky et al, 2017 ; Zhang et al, 2020 ). The packaging of miRNAs into exosomes in the cytoplasm is regulated by a variety of mechanisms, including a neuro-phospholipase-dependent pathway, a heterogeneous ribonucleoprotein-dependent pathway, the 3’-end sequence-dependent pathway of miRNAs, and the miRISC-related pathways (Higa et al, 2014 ; Batool et al, 2020 ). It has been suggested that ex-miRNAs from the CNS may reflect its physiological status and provide a reference for the evaluation of dementia (Zagrean et al, 2018 ).…”

Stumbling on elusive cargo: how isomiRs challenge microRNA detection and quantification, the case of extracellular vesicles

“…Li et al reported an enrichment in 3′-uridylated isoforms for miR-214-3p in osteoclast EVs [73]. Whereas such NTA 3′uridylation was not observed in hepatic cells [74], other studies reported differences at specific nucleotide positions within microRNAs in EV-enriched samples [75][76][77][78], supporting the notion that a sequence heterogeneity may influence the packing of specific microRNAs into EVs, or also promote their cellular retention [67]. More research is required to clarify the conditions that may promote specific isomiR association with EVs.…”

The Progress in Diagnosis and Treatment of Exosomes and MicroRNAs on Epileptic Comorbidity Depression

“…The anti-inflammatory effect of MSC-Exos, especially the inhibition of IL-1b, may have a certain treatment prospect for epileptic comorbidity depression. Moreover, exosomes has been considered to be a vector that promotes inter-cell communication and regulates the cell function by delivering proteins, RNA, and other molecular components, with its nature for biocompatibility, stability in the circulation, biological barrier permeability, low immunogenicity, and low toxicity (7,84). And in vitro model experiments have shown that overexpression of miR-132 can reduce the expression of IL-Ib (39,85).…”

“…Therefore, the diagnosis and treatment of epileptic co-depression is urgent. Nowadays, there are more and more researches linking the pathophysiology of seizures and depression to exosomes and microRNAs (6)(7)(8).…”