Abstract
Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis.
Highlights
Epilepsy is a chronic neurological disease estimated to affect 70 million individuals worldwide (Singh and Trevick, 2016)
To determine the circular RNA (circRNA) transcriptome of Mesial temporal lobe epilepsy (mTLE) patients, RNA was collected from the cortex and hippocampus of mTLE patients and healthy postmortem controls and subjected to RNA sequencing (RNA-seq) (Vangoor et al, 2021)
11914 circRNAs were detected in the cortex and 6947 circRNAs in the hippocampus
Summary
Epilepsy is a chronic neurological disease estimated to affect 70 million individuals worldwide (Singh and Trevick, 2016). MTLE is characterized by hippocampal dysfunction due to impairments in neural excitability and unprovoked temporal lobe seizures (Dalby and Mody, 2001). Due to the progressive nature of mTLE, seizures initially controlled by AEDs can become untreatable over time (French et al, 1993; Camfield and Camfield, 1996; Devinsky et al, 2018). This condition, known as refractory epilepsy, is estimated to affect 70–80% of mTLE patients (Benbadis and Semah, 1999; Kurita et al, 2016). Refractory patients experience a severe condition in which the occurrence of disabling seizures occurs along with other comorbidities such as depression, anxiety and cognitive deterioration (Laxer et al, 2014). There is an urgent need for improved insight into the pathogenesis of mTLE to develop new treatments for this disabling disease
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