Zebrafish as an Innovative Tool for Epilepsy Modeling: State of the Art and Potential Future Directions

Abstract

This article discusses the potential of Zebrafish (ZF) (Danio Rerio), as a model for epilepsy research. Epilepsy is a neurological disorder affecting both children and adults, and many aspects of this disease are still poorly understood. In vivo and in vitro models derived from rodents are the most widely used for studying both epilepsy pathophysiology and novel drug treatments. However, researchers have recently obtained several valuable insights into these two fields of investigation by studying ZF. Despite the relatively simple brain structure of these animals, researchers can collect large amounts of data in a much shorter period and at lower costs compared to classical rodent models. This is particularly useful when a large number of candidate antiseizure drugs need to be screened, and ethical issues are minimized. In ZF, seizures have been induced through a variety of chemoconvulsants, primarily pentylenetetrazol (PTZ), kainic acid (KA), and pilocarpine. Furthermore, ZF can be easily genetically modified to test specific aspects of monogenic forms of human epilepsy, as well as to discover potential convulsive phenotypes in monogenic mutants. The article reports on the state-of-the-art and potential new fields of application of ZF research, including its potential role in revealing epileptogenic mechanisms, rather than merely assessing iatrogenic acute seizure modulation.

Toward the use of novel alternative methods in epilepsy modeling and drug discovery

“…Among them, organotypic brain slice cultures (OSCs), Induced pluripotent Stem Cells (iPSC) and organoids appear as relevant models for new antiseizure drug candidates screening. On another hand, several models not classified as animals larval stage of Danio rerio ( 70 ) or non-vertebrates C. elegans ( 71 , 72 ) and Drosophila melanogaster ( 73 ), traditionally used in basic research on embryonic development, have proven valuable in epilepsy research. This is because these models allow for high-throughput pharmacological screening, enabling the simultaneous evaluation of a large number of samples, the automated analysis of different phenotypes in short times, and the generation of avatars of human patients for the testing of new therapies.…”

“…The main sections in which zebrafish brain is subdivided include forebrain, midbrain and hindbrain/spinal cord. During early development, further subdivisions occur, giving rise to specialized structures in the adult brain which can also be found in rodent models and humans: pallium, subpallium, thalamus, and cerebellum ( 70 ). Moreover, some structures are highly homologous between humans and zebrafish, including the habenula ( 129 ), striatum, basal ganglia ( 130 , 131 ), and cerebellum ( 132 ).…”

CircRNA‐associated ceRNA regulatory networks as emerging mechanisms governing the development and biophysiopathology of epilepsy

“…A notable proportion of cases fall under the category of acquired epilepsy, despite the fact that the underlying mechanisms of epileptic seizures remain largely unidentified and idiopathic factors are prevalent. The initiation and progression of epileptogenesis, ultimately leading to unprovoked seizures, are frequently associated with prior neurological injuries in this particular form of epilepsy 5 …”

Imaging Approaches to Investigate Pathophysiological Mechanisms of Brain Disease in Zebrafish

“…This pivotal feature, combined with the ease of genetic manipulation typical of this animal model, allows for the rapid generation of mutant zebrafish lines carrying, on orthologous genes, human or de novo mutations associated with a pathological phenotype. It is thus feasible to model in zebrafish a great number of both common and rare hereditary pathologies affecting human CNS, such as epilepsies [ 15 , 16 , 17 , 18 ], familial Alzheimer’s disease [ 19 ], and autism spectrum disorder (ASD) [ 20 , 21 ], to cite just a few. Furthermore, zebrafish show homologies with humans concerning the behavioral sphere, too.…”