Author Type

Graduate Student

Date of Award

Fall 11-9-2025

Document Type

Dissertation

Publication Status

Version of Record

Submission Date

January 2026

Department

Biological Sciences

College Granting Degree

Charles E. Schmidt College of Science

Degree Name

Doctor of Philosophy (PhD)

Thesis/Dissertation Advisor [Chair]

Kenneth Dawson-Scully

Thesis/Dissertation Co-Chair

William Hahn

Abstract

Epilepsy is a chronic neurological disorder characterized by recurrent seizures that affect over 50 million people worldwide, including more than 3.5 million in the United States. Seizures arise from a disrupted balance between excitation and inhibition. Although antiepileptic drugs (AEDs) remain the primary treatment to restore the excitation and inhibition balance, approximately 30% of patients experience drug-resistant epilepsy, highlighting the need for additional antiseizure medications. The Caenorhabditis elegans electroshock assay was developed in relative alignment with the rodent maximal electroshock seizure (MES) test, the gold standard for preclinical AED screening, provides a cost-effective platform for prescreening candidate AEDs.

This work advances the C. elegans electroshock assay in two ways. First, iterative hardware refinements were applied to the conventional assay methodology to improve chamber stability, image clarity, and consistency of alignment. Second, a polydimethylsiloxane (PDMS) microfluidic platform was developed to enhance image resolution and clarity, overcoming the limitations of the conventional tube-based setup. This device also reduced worm handling, minimized variability, and enabled higher throughput under uniform conditions. In addition, a machine learning-based analysis pipeline was constructed to track behavior and is designed to generate quantitative measures of seizure recovery, providing a framework for unbiased analysis.

This work also investigated the antiseizure effects of both known and novel compounds to demonstrate the utility of the assay improvements. A known GABAA receptor agonist isoguvacine reduced seizure-like behavior across wildtype worms and in unc-25, but not in unc-49, supporting the microfluidic platform’s sensitivity to known GABAA receptor agonists. In parallel, Resveramorph-3, a novel resveratrol-inspired compound, attenuated the PTZ extended recovery time after electroshock in prior conventional work and produced recovery in the microfluidic platform, underscoring directional cross-platform reproducibility and validation.

Collectively, this work refines the conventional assay while establishing a distinct microfluidics approach, together improving reproducibility, scalability, and objectivity. By integrating engineering improvements, a validated microfluidic design, and framework for automated behavioral analysis, this work provides a platform positioned to accelerate prescreening of candidate AEDs and support efforts to expand treatment options for drug-resistant epilepsy.

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