Large-scale imaging of epileptic networks in zebrafish

About This Grant

Project Summary/Abstract Epilepsy can be genetic. In many cases, genetic epilepsies present with severe drug-resistant seizures. Comorbid conditions in these patients can include cognitive deficit, impaired communication, autism, mood disorders, and significant developmental delay. Although de novo single gene mutations were identified for many genetic epilepsies, our overall understanding of these conditions remains limited. We generated a library of single-gene mutant zebrafish models and used sensitive electrophysiology screening to uncover epilepsy phenotypes. Several zebrafish models exhibiting spontaneous electrographic seizure activity were identified. Here we propose studies using models for SCN1A and ARX mutations. These vertebrate models recapitulate epilepsy endophenotypes and represent a sub-category of epileptic encephalopathies associated with interneuron dysfunction or loss, respectively. As an experimental model, zebrafish (Danio rerio) possess tremendous potential to advance our understanding of brain networks at a scale not possible with rodent models. Building on our extensive experience developing zebrafish models and technologies for epilepsy research, two specific aims utilizing scn1a and arxa mutants are proposed: (i) to analyze brain-wide seizure dynamics in epileptic zebrafish and (ii) to understand how interneurons regulate seizure dynamics in epileptic zebrafish. Techniques will include fast volumetric calcium imaging, multiplexed hybridization chain reaction protocols, and in vivo electrophysiology. This research is significant because it merges state-of-the-art calcium imaging approaches with clinically relevant zebrafish models, to provide fundamental insights into these debilitating conditions.