Building a zebrafish toolkit for investigating the pathobiology of epilepsy and identifying new treatments for epileptic seizures

Recent advances in genomics and genome sequencing technologies provide a wealth of DNA sequence data that sheds new light on the causes of epilepsy. Animal models help to elucidate the biological significance of such disease-associated DNA sequence variation by enabling functional relationships between disease genotypes and phenotypes to be defined. Here I review the unique combination of attributes that is allowing the zebrafish to play increasingly prominent roles in investigating the mechanisms underlying epilepsy and in discovering new drugs to treat this condition. New techniques for genome editing now allow the zebrafish genome to be engineered to recapitulate key elements of the patterns of genomic variation that are observed in epilepsy patients. Moreover, a sophisticated range of imaging technologies enables spatio-temporal patterns of neural activity to be visualised in the intact zebrafish nervous system with single-cell levels of resolution. These technologies, together with refined techniques for electrophysiological analysis and non-invasive modulation of specific neuronal circuit functions, allow the impacts of defined genetic variation on in vivo patterns of neural activity to be analysed in unprecedented depth. The pharmacological tractability of the zebrafish, and the amenability of its embryonic and larval stages to high throughput phenotype analysis, are also enabling advances in anti-epileptic drug discovery. Combining such pharmacological screening approaches with new tools for genome editing, live imaging, electrophysiology, conditional manipulation of circuit activity and behavioural analysis of zebrafish, could facilitate step changes in both understanding of epileptogenesis and in vivo discovery of new and improved anti-epileptic drugs.