Publication Date

April 2017

Advisor(s)

Janice Naegele

Major

Neuroscience & Behavior

Language

English (United States)

Abstract

Despite the growing number of treatments for epilepsy, patients with drug resistant epilepsy still have limited options beyond invasive surgical intervention. Recent developments in animal research have highlighted the therapeutic potential of optogenetic and chemogenetic therapy. While the anticonvulsant effect of optogenetic silencing techniques have been robustly demonstrated in mouse models of epilepsy, the same effect has not been as extensively explored with chemogenetic silencing techniques. We investigated whether hippocampal expression of a modified drug-activated glycine receptor reduced limbic seizures. Adult mice received stereotaxic injections of an AAV2 containing mutated glycine receptor (iGlyR) activated by Ivermectin (IVM) into multiple sites in the hippocampal formation. After allowing several weeks for viral expression, acute seizures were induced in mice using a modified pilocarpine seizure induction protocol. Seizure activity was monitored by continuous video-EEG recordings from several hours prior to IVM injection to four hours after pilocarpine injection. Serenia Pro Seizure detection software was used to quantify the latency, incidence, and severity of the seizures. Viral-mediated expression was analyzed and quantified based on immunohistochemical staining and confocal microscopy. Treated groups displayed decreased time to ictal events compared to all controls. The high dose treated group displayed increased number of seizures per minute before status epilepticus or death and decreased seizure durations. We observed expression of iGlyR in all layers of the dentate gyrus and cornus ammonis. These results indicate successful modulation of ictal activity through the activation of iGlyR during pilocarpine induced limbic seizures.

Available for download on Wednesday, April 15, 2020

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