Antagonizing Increased miR-135a Levels at the Chronic Stage of Experimental TLE Reduces Spontaneous Recurrent Seizures

• Published in: The Journal of neuroscience Vol. 39; no. 26; pp. 5064 - 5079
• Main Authors: Vangoor, Vamshidhar R, Reschke, Cristina R, Senthilkumar, Ketharini, van de Haar, Lieke L, de Wit, Marina, Giuliani, Giuliano, Broekhoven, Mark H, Morris, Gareth, Engel, Tobias, Brennan, Gary P, Conroy, Ronan M, van Rijen, Peter C, Gosselaar, Peter H, Schorge, Stephanie, Schaapveld, Roel Q J, Henshall, David C, De Graan, Pierre N E, Pasterkamp, R Jeroen
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 26.06.2019
• Subjects: Antiepileptic agents; Brain; Convulsions & seizures; Dendritic spines; Deregulation; Disease control; Epilepsy; Gene expression; Gene sequencing; Immunoprecipitation; Neurological diseases; Pathogenesis; Post-transcription; Regulators; Ribonucleic acid; RNA; Seizures; Spine; Synaptic density; Synaptic plasticity; Target recognition; Temporal lobe; Mef2; RNA sequencing; epilepsy; miRNA; antagomirs; mesial temporal lobe epilepsy
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3014-18.2019

Mesial temporal lobe epilepsy (mTLE) is a chronic neurological disease characterized by recurrent seizures. The antiepileptic drugs currently available to treat mTLE are ineffective in one-third of patients and lack disease-modifying effects. miRNAs, a class of small noncoding RNAs which control gene expression at the post-transcriptional level, play a key role in the pathogenesis of mTLE and other epilepsies. Although manipulation of miRNAs at acute stages has been reported to reduce subsequent spontaneous seizures, it is uncertain whether targeting miRNAs at chronic stages of mTLE can also reduce seizures. Furthermore, the functional role and downstream targets of most epilepsy-associated miRNAs remain poorly understood. Here, we show that is selectively upregulated within neurons in epileptic brain and report that targeting using antagomirs after onset of spontaneous recurrent 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 , including Mef2 proteins are key regulators of excitatory synapse density. Mef2a and show reciprocal expression regulation in human (of both sexes) and experimental TLE, and regulates dendritic spine number and type through Mef2. Together, our data show that is target for reducing seizure activity in chronic epilepsy, and that deregulation of in epilepsy may alter expression and thereby affect synaptic function and plasticity. miRNAs are post-transcriptional regulators of gene expression with roles in the pathogenesis of epilepsy. However, the precise mechanism of action and therapeutic potential of most epilepsy-associated miRNAs remain poorly understood. Our study reveals dramatic upregulation of the key neuronal miRNA in both experimental and human mesial temporal lobe epilepsy. Silencing in experimental temporal lobe epilepsy reduces seizure activity at the spontaneous recurrent seizure stage. These data support the exciting possibility that miRNAs can be targeted to combat seizures after spontaneous seizure activity has been established. Further, by using unbiased approaches novel neuronal targets of , including members of the Mef2 protein family, are identified that begin to explain how deregulation of may contribute to epilepsy.