Mesial temporal lobe epilepsy (MTLE) is a particularly devastating form of human epilepsy with significant incidence of medical intractability. MicroRNAs (miRs) are small, noncoding RNAs that regulate the posttranscriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of MTLE development. To study the dynamic expression patterns of brain-specific miR-124 and miR-134 and inflammation-related miR-132 and miR-21, we performed qPCR on the hippocampi of immature rats at 25 days of age. Expressions were monitored in the three stages of MTEL and in the control hippocampal tissues corresponding to the same timeframes. A similar expression method was applied to hippocampi obtained from children with MTLE and normal controls. The expression patterns of miR-124 and miR-134 nearly showed the same dynamics in the three stages of MTLE development. On the other hand, miR-132 and miR-21 showed significant upregulation in acute and chronic stages, while in the latent stage, miR-132 was upregulated and miR-21 was downregulated. The four miRs were upregulated in hippocampal tissues obtained from children with MTLE. The significant upregulation of miR-124 and miR-134 in the seizure-related stages and children suggested that both can be potential targets for anticonvulsant drugs in the epileptic developing brains, while the different expression patterns of miR-132 and miR-21 may suggest different functions in MTLE pathogenesis.
"Indeed, miRNA responses to seizures often display sharp temporal changes (Sano et al. 2012). Given the independent findings of miR-134 upregulation in the hippocampus of children and adults with TLE (Jimenez- Mateos et al. 2012; Peng et al. 2013), these findings establish increased miR-134 as a conserved molecular response to seizures in the brain. Fig. 6 Reduced clinical seizures and mortality in Ant-134 mice subject to SE. a, b Graphs showing average Racine scores for Scr (n = 11) and Ant-134 (n = 12) animals, a during 90 min after PILO injection and b recorded after lorazepam termination of SE (**P \ 0.01; *P \ 0.05, compared to Scr). "
[Show abstract][Hide abstract] ABSTRACT: Emerging data support roles for microRNA (miRNA) in the pathogenesis of various neurologic disorders including epilepsy. MicroRNA-134 (miR-134) is enriched in dendrites of hippocampal neurons, where it negatively regulates spine volume. Recent work identified upregulation of miR-134 in experimental and human epilepsy. Targeting miR-134 in vivo using antagomirs had potent anticonvulsant effects against kainic acid-induced seizures and was associated with a reduction in dendritic spine number. In the present study, we measured dendritic spine volume in mice injected with miR-134-targeting antagomirs and tested effects of the antagomirs on status epilepticus triggered by the cholinergic agonist pilocarpine. Morphometric analysis of over 6,400 dendritic spines in Lucifer yellow-injected CA3 pyramidal neurons revealed increased spine volume in mice given antagomirs compared to controls that received a scrambled sequence. Treatment of mice with miR-134 antagomirs did not alter performance in a behavioral test (novel object location). Status epilepticus induced by pilocarpine was associated with upregulation of miR-134 within the hippocampus of mice. Pretreatment of mice with miR-134 antagomirs reduced the proportion of animals that developed status epilepticus following pilocarpine and increased animal survival. In antagomir-treated mice that did develop status epilepticus, seizure onset was delayed and total seizure power was reduced. These studies provide in vivo evidence that miR-134 regulates spine volume in the hippocampus and validation of the seizure-suppressive effects of miR-134 antagomirs in a model with a different triggering mechanism, indicating broad conservation of anticonvulsant effects.
Brain Structure and Function 05/2014; 220(4). DOI:10.1007/s00429-014-0798-5 · 5.62 Impact Factor
"MiR-134 is another activity-regulated miRNA that has been found to be upregulated after SE in kainate and pilocarpine models of SE (Jimenez-Mateos et al., 2011, 2012; Peng et al., 2013). Levels of miR-134 were also confirmed to be increased in the RISC in Ago2 pull down experiments after SE and there were lower protein levels of two validated targets (Jimenez-Mateos et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: MicroRNA (miRNA) are an important class of non-coding RNA which function as post-transcriptional regulators of gene expression in cells, repressing and fine-tuning protein output. Prolonged seizures (status epilepticus, SE) can cause damage to brain regions such as the hippocampus and result in cognitive deficits and the pathogenesis of epilepsy. Emerging work in animal models has found that SE produces select changes to miRNAs within the brain. Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE. The miRNA changes that accompany SE are predicted to impact levels of multiple proteins involved in neuronal morphology and function, gliosis, neuroinflammation, and cell death. miRNA expression also displays select changes in the blood after SE, supporting blood genomic profiling as potential molecular biomarkers of seizure-damage or epileptogenesis. Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs. Targeting miR-34a, miR-132 and miR-184 has been reported to alter seizure-induced neuronal death, whereas targeting miR-134 was neuroprotective, reduced seizure severity during status epilepticus and reduced the later emergence of recurrent spontaneous seizures. These studies support roles for miRNAs in the pathophysiology of status epilepticus and miRNAs may represent novel therapeutic targets to reduce brain injury and epileptogenesis.
"Subsequently, with an increasing interest in the possible role of regulatory RNAs in epilepsy, large-scale analyzes of miRNA expression profile by either hybridization or TaqMan® arrays were undertaken in the hippocampus of animals with induced epilepsy (Liu et al., 2010b; Jimenez-Mateos et al., 2011; Song et al., 2011; Hu et al., 2012; McKiernan et al., 2012b; Pichardo-Casas et al., 2012; Peng et al., 2013; Risbud and Porter, 2013). Analyzes were performed on the lithium-pilocarpine model (Song et al., 2011; Hu et al., 2012), systemic pilocarpine (Risbud and Porter, 2013), systemic kainic acid (Liu et al., 2010b; McKiernan et al., 2012b; Pichardo-Casas et al., 2012), intra-amygdala kainic acid (Jimenez-Mateos et al., 2011), with time points ranging from a few hours (McKiernan et al., 2012b) to months after status epilepticus (Song et al., 2011; Hu et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Epilepsy, one of the most frequent neurological disorders, represents a group of diseases that have in common the clinical occurrence of seizures. The pathogenesis of different types of epilepsy involves many important biological pathways; some of which have been shown to be regulated by microRNAs (miRNAs). In this paper, we will critically review relevant studies regarding the role of miRNAs in epilepsy. Overall, the most common type of epilepsy in the adult population is temporal lobe epilepsy (TLE), and the form associated with mesial temporal sclerosis (MTS), called mesial TLE, is particularly relevant due to the high frequency of resistance to clinical treatment. There are several target studies, as well few genome-wide miRNA expression profiling studies reporting abnormal miRNA expression in tissue with MTS, both in patients and in animal models. Overall, these studies show a fine correlation between miRNA regulation/dysregulation and inflammation, seizure-induced neuronal death and other relevant biological pathways. Furthermore, expression of many miRNAs is dynamically regulated during neurogenesis and its dysregulation may play a role in the process of cerebral corticogenesis leading to malformations of cortical development (MCD), which represent one of the major causes of drug-resistant epilepsy. In addition, there are reports of miRNAs involved in cell proliferation, fate specification, and neuronal maturation and these processes are tightly linked to the pathogenesis of MCD. Large-scale analyzes of miRNA expression in animal models with induced status epilepticus have demonstrated changes in a selected group of miRNAs thought to be involved in the regulation of cell death, synaptic reorganization, neuroinflammation, and neural excitability. In addition, knocking-down specific miRNAs in these animals have demonstrated that this may consist in a promising therapeutic intervention.
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