Abstract
Mesial temporal lobe epilepsy (mTLE) is a common form of epilepsy and is characterized by recurrent spontaneous seizures originating from the temporal lobe. The majority of mTLE patients develop pharmacoresistance to available anti-epileptic drugs (AEDs) while exhibiting severe pathological changes that can include hippocampal atrophy, neuronal death, gliosis and chronic seizures. The molecular mechanisms leading to mTLE remain incompletely understood, but are known to include defects in post-transcriptional gene expression regulation, including in non-coding RNAs (ncRNAs). Circular RNAs (circRNAs) are a class of recently rediscovered ncRNAs with high levels of expression in the brain and proposed roles in diverse neuronal processes. To explore a potential role for circRNAs in epilepsy, RNA-sequencing (RNA-seq) was performed on hippocampal tissue from a rat perforant pathway stimulation (PPS) model of TLE at different post-stimulation time points. This analysis revealed 218 differentially expressed (DE) circRNAs. Remarkably, the majority of these circRNAs were changed at the time of the occurrence of the first spontaneous seizure (DOFS). The expression pattern of two circRNAs, circ_Arhgap4 and circ_Nav3, was further validated and linked to miR-6328 and miR-10b-3p target regulation, respectively. This is the first study to examine the regulation of circRNAs during the development of epilepsy. It reveals an intriguing link between circRNA deregulation and the transition of brain networks into the state of spontaneous seizure activity. Together, our results provide a molecular framework for further understanding the role and mechanism-of-action of circRNAs in TLE.
Highlights
Epilepsy is considered the most common chronic brain disease and is estimated to affect more than 50 million people worldwide (Ngugi et al, 2010)
Here we investigate for the first time how a specific circular RNA (circRNA)/miRNA/messenger RNA targets (mRNA) network is deregulated at early stages of experimental epilepsy using a perforant pathway stimulation (PPS) rat model of temporal lobe epilepsy (TLE)
In vivo PPS is characterized by high survival rates and low variability of hippocampal injury while displaying major pathophysiological hallmarks of Mesial temporal lobe epilepsy (mTLE), such as hippocampal atrophy, gliosis, hippocampal region-specific neuronal death resembling International League Against Epilepsy (ILAE) type 1, and recurrent spon taneous seizures (Norwood et al, 2010)
Summary
Epilepsy is considered the most common chronic brain disease and is estimated to affect more than 50 million people worldwide (Ngugi et al, 2010). Focal epilepsies account for 60% of all epilepsy forms (Devinsky et al, 2018). MTLE is a frequent form of focal epilepsy and is characterized by pathological manifestations that include hippocampal atrophy, neuronal death, gliosis and spontaneous seizures. In mTLE, the proportion of patients who do not become seizure free with AEDs is around 70–90% (Benbadis and Semah, 1999; Kurita et al, 2016). This condition, known as “refractory epilepsy,” highlights the need for the discovery of new molecular pathways that can be therapeutically targeted in TLE
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