Mesial temporal lobe epilepsy (mTLE) is normally a chronic neurological disease characterized by recurrent seizures
August 27, 2020
Mesial temporal lobe epilepsy (mTLE) is normally a chronic neurological disease characterized by recurrent seizures. using antagomirs after onset of spontaneous recurrent GSK2795039 GSK2795039 seizures can reduce seizure activity at the chronic stage of experimental mTLE in male mice. Further, by using an unbiased approach combining immunoprecipitation and RNA sequencing, we identify several novel neuronal targets of show reciprocal expression regulation in human (of both sexes) and experimental TLE, and regulates dendritic spine number and type through Mef2. Together, our data display that is focus on for reducing seizure activity in chronic epilepsy, which deregulation of in epilepsy might alter manifestation and affect synaptic function and plasticity thereby. SIGNIFICANCE Declaration miRNAs are post-transcriptional regulators of gene manifestation with tasks in the pathogenesis of epilepsy. Nevertheless, the precise system of actions and restorative potential of GSK2795039 all epilepsy-associated miRNAs stay poorly understood. Our research reveals dramatic upregulation of the main element neuronal miRNA in both human being and experimental mesial temporal lobe epilepsy. Silencing in experimental temporal lobe epilepsy decreases seizure activity in the spontaneous repeated seizure stage. These data support the thrilling probability that miRNAs could be targeted to fight seizures after spontaneous seizure activity continues to be established. Further, through the use of unbiased approaches book neuronal focuses on of may donate to epilepsy. continues to be found out to elicit beneficial results in the histopathology level and on seizure activity (Gross et al., 2016; Henshall et al., 2016; Iori et al., 2017). Not surprisingly progress, the systems by which most miRNAs influence seizures and/or epileptogenesis stay unknown. Furthermore, whether manipulation of miRNAs at later, chronic stages of epilepsy has therapeutic effects is an important but largely unresolved question. Previously, we have shown that a significant number of miRNAs are upregulated or downregulated in hippocampal tissue of human mTLE patients (Kan et al., 2012). Of those miRNAs, is of particular interest as it is known to control neuronal morphology and synaptic function. For example, modulates glutamatergic neurotransmission by regulating Complexin1/2 in the amygdala (Mannironi et al., 2018). Furthermore, promotes developmental axon growth and branching, cortical neuronal migration, and regeneration of RGC axons following optic nerve injury in adult mice (van Battum et al., 2018). Because of these biological effects of and the strong increase in in mTLE patients, we further investigated the potential role of in mTLE pathogenesis. Our data show that expression is specifically increased during the chronic stage of experimental TLE and that inhibiting at this stage reduces spontaneous seizure activity. These data show one of the first examples that inhibiting an miRNA at chronic stages of experimental TLE has therapeutic effects on spontaneous seizure activity. As a first step toward NBR13 understanding how influences seizure activity, we identify the activity-dependent transcription Mef2a as a direct neuronal target. Further, our results confirm reciprocal regulation of and expression in epilepsy and reveal that can regulate dendritic spine morphology and number through Mef2. Materials and Methods Animals. All animal experiments were performed according to the institutional guidelines and approved by (1) the Research Ethics Committee of the Royal College of Surgeons in Ireland; ethics: REC 842; and HPRA (Health Products Regulatory Authority) AE19127/P001, or (2) the local ethical animal experimentation committee (Dierexperimenten Ethische Commissie) of the University Medical Center Utrecht (protocol numbers DEC 2014.I.01.005, 527-16-532-03-07). C57bl6J mice (male and female) were obtained from Charles Rivers Laboratories. Intra-amygdala kainate (IAK) mouse model. Animals were handled according to institutional guidelines, and experiments were reviewed and approved by Royal College of Surgeons in Ireland (REC 842), under a license from the Department of Health (Health Products Regulatory Authority, AE19127/001), Dublin, Ireland and reviewed and approved by the ethical animal experimentation committee (Dierexperimenten Ethische Commissie) of University Medical Center Utrecht under the project license AVD115002016532 (protocol 527-16-532-03-07). Status epilepticus (SE) induction, EEG recording, and analysis were performed as previously described (Mouri et al., 2008; Jimenez-Mateos et al., 2012). Quickly, for the long-term monitoring (24/7 video/EEG), man mice had been implanted with telemetric EEG transmitters (Data Systems International) for bilateral documenting on both mind hemispheres with four calculating electrodes. EEG data had been obtained using Ponemah acquisition software program (edition 5.20, Data Systems International), and F20-EET EEG.