Age Bias in Zebrafish Models of Epilepsy: What Can We Learn From Old Fish?

Abstract

Zebrafish are a powerful tool for investigating epilepsy. Mammalian seizures can be recapitulated molecularly, behaviorally, and electrophysiologically, using a fraction of the resources required for experiments in mammals. Larval zebrafish offer exceptionally economical and high-throughput approaches and are amenable to state-of-theart genetic engineering techniques, providing valuable transgenic models of human diseases. For these reasons, larvae tend to be chosen for studying epilepsy, but the value of adult zebrafish may be underappreciated. Zebrafish exhibit transient larvaladult duality. The incompletely developed neural system of larval zebrafish may limit the translation of complex neurological disorders. Larval zebrafish go through dynamic changes during ontogenesis, whereas adult zebrafish are physiologically more stable. Adult zebrafish have a full range of complex brain structures and functions, such as an endothelial blood-brain barrier and adult neurogenesis, both are significant factors in epilepsy research. This review highlights the differences between larval and adult zebrafish that should be considered in pathophysiological and pharmacological studies of epilepsy.

GABAAα Subunit Control of Hyperactive Behavior in Developing Zebrafish

“…Abnormalities in GABAA receptor inhibition are observed in genetic and acquired epilepsies, drugs that block these receptors, like PTZ, cause seizures, and drugs that enhance GABAA receptor inhibition are potent anticonvulsants. In zebrafish, PTZ application is an established seizure model, and loss-of-function mutations in γ2 and β3 cause larval hyperactive behavior and/or neuronal activity that model the epilepsies caused by mutations in their human orthologs (Baraban et al 2005;Baxendale et al 2012;Liao et al 2019;Yang et al 2019;Cho et al 2020). Similarly, mutations in zebrafish α1 cause light-triggered, hyperactive behavior in juvenile fish (older than ~5 weeks) that seems to model epilepsy caused by reduced α1 function (Samarut et al 2018).…”

“…Early larval-stage zebrafish, ~2-10 days post-fertilization, are a leading model for locomotor neural network analysis, and GABAA receptors regulate locomotion in this system. Bath application of GABAA receptor antagonists, such as pentylenetetrazole (PTZ), induces hyperactive swimming, meaning a dramatic increase which is also recognized as an epileptic seizure model (Baraban et al 2005;Baxendale et al 2012;Cho et al 2020). Zebrafish harbor an array of GABAA subunits similar to mammals, with 23 identified subunits (Cocco et al 2017;Monesson-Olson et al 2018), however few mutants have been identified as important for locomotion.…”

THE ZEBRAFISH ANIMAL MODEL (Danio rerio) USED FOR DIFFERENT THERAPEUTIC APPROACHES FOR THE SUPPRESSION OF EPILEPTIC CRISIS: A SYSTEMATIC REVIEW

“…Brains of more complex mammals and organisms for the purposes of genetic modeling, including zebrafish, have been widely studied and zebrafish has gained great popularity in behavioral neuroscience and research in psychopharmacology (9) In addition, the zebrafish model system offers large-scale screening and resembles the complexity of the central nervous system (CNS) (10). Interestingly, the genetic compositions of zebrafish are comparable to humans with 70% genetic similarity, while 84% of the genes known for human diseases are widely expressed in zebrafish (11).…”

Antiepileptic Drugs Cause Lethal, Sublethal, Teratogenic Effects and Morphometric Parameters on Embryos and Larvae of Zebrafish (Danio Rerio)

“…Os efeitos teratogênicos revelaram malformação da cabeça INTRODUCTION Antiepileptic drugs are among the most common teratogenic drugs prescribed to women of childbearing age (Shihmanab, et al, 2019;Li et al, 2020). Approximately 1 million women of childbearing age have epilepsy, being important to highlight that the continued use of antiepileptic drugs is recommended to reduce the maternal and fetal trauma associated with seizures in the USA (Patel and Pennell, 2016;Kim et al, 2019;Cho et al, 2020). However, prenatal exposure to antiepileptic drugs can cause growth retardation, major congenital malformations, and intelligence deficits in the developing fetus (Kim et al, 2019;Patel and Pennell, 2016;Bhakta et al, 2015).…”