Zebrafish models of developmental epileptic encephalopathy accurately reflect clinical electrographic biomarkers.

Abstract

OBJECTIVE: Developmental epileptic encephalopathies (DEEs) are epilepsy conditions characterized by significant severity and treatment challenges. Spectral components of the encephalogram (EEG) may provide a valuable biomarker of epileptic severity. Features of this signal include alterations in power spectral density, interictal epileptiform discharges, and high-frequency oscillations (HFOs). These findings largely derive from temporal lobe epilepsy patients and rodent models. Evidence for altered spectral EEG components in preclinical DEE models is rare. Here, we analyzed electrophysiology data from zebrafish genetically engineered to mimic human DEE conditions. METHODS: Local field potential (LFP) recordings from six zebrafish mutant lines (arxa, gabrb3, grin1b, pnpo, scn1lab, and strada) with recurrent ictal-like epileptiform discharges were analyzed. HFOs were identified using an automated MATLAB program (RippleLab). Fast Fourier transformations and analysis of interictal epileptiform discharges (IEDs) were also performed using MATLAB software. RESULTS: Fast Fourier transform analysis of LFP signals revealed increased power in the delta frequency band (0.5-3.5 Hz) for scn1lab, grin1b, and gabrb3 mutant lines. We also report the consistent presence of HFO events (>250 Hz) and altered IED dynamics in arxa, gabrb3, grin1b, pnpo, scn1lab, and strada mutant lines. SIGNIFICANCE: This study provides compelling evidence that spectral signatures of abnormal brain activity commonly observed in humans can be recapitulated in larval zebrafish. These electrical events in zebrafish could serve as important biomarkers. These observations not only reinforce the value of zebrafish as an important preclinical animal model for epilepsy research but also suggest new avenues for deconstruction of pathological epileptic networks in an experimental setting.