Abstract
The study of sources and spatiotemporal evolution of ictal bursts is critical for the mechanistic understanding of epilepsy and for the validation of anti-epileptic drugs. Zebrafish is a powerful vertebrate model representing an excellent compromise between system complexity and experimental accessibility. We performed the quantitative evaluation of the spatial recruitment of neuronal populations during physiological and pathological activity by combining local field potential (LFP) recordings with simultaneous 2-photon Ca2+ imaging. We developed a method to extract and quantify electrophysiological transients coupled with Ca2+ events and we applied this tool to analyze two different epilepsy models and to assess the efficacy of the anti-epileptic drug valproate. Finally, by cross correlating the imaging data with the LFP, we demonstrated that the cerebellum is the main source of epileptiform transients. We have also shown that each transient was preceded by the activation of a sparse subset of neurons mostly located in the optic tectum.
Highlights
Epilepsy is one of the most common chronic neurological disorders and affects nearly 65 million people worldwide [1]
We show how the statistics of the time series provided by the recordings of local field potential (LFP) and Ca2+ imaging can be used to classify activity in zebrafish either when seizures are induced by exposure to the pro-convulsant GABAA R antagonist pentylentetrazole (PTZ) [24], or by knocking down the kcnj10a gene, as in a model of the EAST (Epilepsy, Ataxia, Sensorineural deafness, and Tubulopathy) /SeSAME (Seizures, Sensorineural deafness, Ataxia, intellectual (Mental) disability, and Electrolyte imbalance) syndrome [11]
We analyzed three experimental groups: wild-type (WT) larvae, WT larvae treated with PTZ as a model of pharmacologically induced seizures and the morphants of kcnj10a as a model of EAST syndrome [11], a brain disease characterized by spontaneous seizures
Summary
Epilepsy is one of the most common chronic neurological disorders and affects nearly 65 million people worldwide [1]. Zebrafish is an emerging model for the study of human neurological disorders, and for the identification of potential therapeutic targets [3,4]. The molecular genetics of epilepsy cohorts is revealing an increasing number of genetic mutations that leads to the neurological disease. The functional study of the mutated genes can exploit the simplicity of the zebrafish model [7,8]. Both advanced genome editing [7,9] and the more rapid morpholino technique for the transient knockdown of specific genes [10,11,12] have been adopted to mimic human epileptic conditions in fish.
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