MicroRNA-Mediated Modulation of Electrographic Activity in a Cntnap2 Mouse Model of Epilepsy

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Rishav Mukherjee
Andrew Snider
Meghna Kilaparthi
Christina Gross
Durgesh Tiwari

Abstract

By Rishav Mukherjee, Medical Sciences; Andrew Snider, Cincinnati Children's Hospital and Medical Center; Meghna Kilaparthi, Cincinnati Children's Hospital and Medical Center; Christina Gross, Cincinnati Children's Hospital and Medical Center


Advisor: Durgesh Tiwari



Presentation ID: 143


Abstract: Cntnap2 encodes contactin-associated protein-like 2 and plays a vital role in neuron-glia interaction and action potential propagation. Mutations in Cntnap2 are associated with epilepsy and autism. Cntnap2 knockout mice exhibit seizures and autism related behavioral deficits however the mechanism leading to the network excitability is unknown. MicroRNAs (miRNAs) regulate post-transcriptional expression of mRNA and can be used to regulate gene expression. MiR-324-5p and miR-218-5p are notable miRNAs which are involved regulating seizure susceptibility in mouse models of epilepsy. We used antagomirs (antisense oligonucleotides) to explore the neuroprotective potential of miR-324-5p and miR-218-5p in Cntnap2 a mouse model and analyzed the changes in electrographic activity. Mice were genotyped and investigated at younger (4-6 months) and older (12-16 months) age points to determine age-specific seizure development. Seizures were confirmed using the tail-suspension assay and cortical EEG recordings. Mice were implanted with electrodes and injected with miR-324-5p, miR-218-5p, or scrambled antagomir at both age points, and EEG monitored for a week. Younger mice underwent a kainic acid seizure onset challenge. Results: At younger and older age point miR-324-5p antagomirs delayed the seizure onset and severity and miR-218-5p antagomir-treatment increased seizures and seizure susceptibility compared to SCR control. EEG waveform and spike analysis showed no significant difference in EEG waveforms between antagomir treatment and SCR control (preliminary data). This study demonstrated the potential for miR-mediated regulation of seizures in Cntnap2 KO mice. Ongoing studies will aim to explore the localization of the effects using immunohistochemistry and sleep-wake patterns in EEG activity.

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New Frontiers