MiR-219 Protects Against Seizure in the Kainic Acid Model of Epilepsy

Abstract

Emerging evidence indicates that certain microRNAs (miRNAs) play important roles in epileptogenesis. MiR-219 is a brain-specific miRNA and has been shown to negatively regulate the function of N-methyl-D-aspartate (NMDA) receptors by targeting Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)γ. Herein, we found that the level of miR-219 was decreased in both the kainic acid (KA)-induced epilepsy model and in cerebrospinal fluid specimens of epilepsy patients. Importantly, silencing of miR-219 by its antagomir in vivo resulted in seizure behaviors, abnormal cortical electroencephalogram (EEG) recordings in the form of high-amplitude and high-frequency discharges, and increased levels of CaMKIIγ and an NMDA receptor component, NR1, in a pattern similar to that found in KA-treated mice. Moreover, treatments with the miR-219 agomir in vivo alleviated seizures, abnormal EEG recordings, and decreased levels of CaMKIIγ and NR1 in KA-treated mice. Furthermore, treatment with MK-801, an antagonist of NMDA receptors, significantly alleviated abnormal EEG recordings induced by miR-219 antagomir. Together, these results demonstrate that miR-219 plays a crucial role in suppressing seizure formation in experimental models of epilepsy through modulating the CaMKII/NMDA receptor pathway and that miR-219 supplement may be a potential anabolic strategy for ameliorating epilepsy.

Inhibition of MyD88 Signaling Skews Microglia/Macrophage Polarization and Attenuates Neuronal Apoptosis in the Hippocampus After Status Epilepticus in Mice

“…Consistent with previous studies [6,52,53], our findings indicate that M1 MG/MΦ polarization augments glutamate toxicity, which may lead to apoptosis (and/or other types of cell death) of pyramidal neurons and extensive gliosis, which in turn may underlie, at least in part, the potential occurrence of spontaneous seizures in the chronic phase.…”

“…NMDA receptors play critical roles in epileptic excitotoxicity, and NMDA receptor antagonists have been used to treat refractory seizures [49,50]. NMDA receptor subunit composition has been reported to be altered in epilepsy models [6,[41][42][43][44][45][46][47][48][49][50][51][52][53]. In addition, it has been reported that iNOS acts on mature neurons indirectly, increasing NMDA receptor expression [54].…”

Silencing MicroRNA-155 Attenuates Kainic Acid-Induced Seizure by Inhibiting Microglia Activation

“…As previously described [27], mice were subjected to miR-155 antagomir or NC injection into the right lateral cerebral ventricle (i.c.v., 0.5 mm posterior to the bregma, 1.0 mm lateral to the midsagittal suture, 2.2 mm below the dura matter) using a 10-μL Hamilton syringe at a speed of 0.3 μL/min in a stereotaxic instrument (RWD Life Science, Shenzhen, China). The syringe was held for 10 min after injection.…”

“…The EEGs of all mice were recorded for 2 h after the i.c.v. injection following the method described previously [27]. EEG data were analyzed by Nicolet 1.0 software in which the interference of alternating current was eliminated, and the sensitivity was uniformly adjusted to 20 μV/mm.…”

Performance Metrics for Selecting Single Nucleotide Polymorphisms in Late-onset Alzheimer’s Disease

“…GWASs in east-Asian populations are limited; only one Japanese GWAS12 has been conducted. Although several studies in China have validated SNPs identified from GWASs in the western countries131415, no GWAS has been conducted in a Chinese population using microarray chips customized for Chinese populations. For LOAD, some genes have been consistently identified across GWASs, and these genes mainly belong to three biological pathways, i.e., the metabolic, trafficking, and signaling pathways161718.…”