Targeting MMP-9 activation after early-life seizures reduces seizure susceptibility and memory deficits in a larval zebrafish model

Abstract

One in 26 Americans experience seizures, with a high incidence occurring in the first years of life. Chronic consequences of prolonged early-life seizures (ELS) in humans and rodent models vary, but can include the development of epilepsy (spontaneous, recurrent seizures) and cognitive impairment. Because it is not clear how seizures might lead to these consequences, no therapeutic strategy exists to prevent or predict them. Here, we optimized a larval zebrafish ELS model to assess a therapeutic approach targeting post-ELS sequelae. Using increased seizure susceptibility as a readout of the epileptogenic process and a novel object recognition task to assess memory, we found that two weeks after a three-day ELS induction paradigm, zebrafish were significantly more susceptible to seizures and showed a significant memory deficit. Therefore, we next used this model to identify and target underlying mechanisms. After observing an acute post-ELS increase in mmp9 gene expression, we pharmacologically inhibited the conversion of pro-MMP-9 to active MMP-9 after ELS using JNJ0966, and tested subsequent seizure susceptibility and memory two weeks later. Preventing formation of active MMP-9 for the first hour post-ELS was sufficient to return memory and seizure susceptibility readouts to that of clutch mate controls. This study provides novel insight into the development of ELS sequelae and presents a promising model for moving ELS research forward, demonstrating seizure susceptibility, memory assessment, therapeutic targeting, and pharmacological testing in a simplified model.