Zebrafish Models of Neurodevelopmental Disorders: Limitations and Benefits of Current Tools and Techniques

Abstract

For the past few years there has been an exponential increase in the use of animal models to confirm the pathogenicity of candidate disease-causing genetic variants found in patients. One such animal model is the zebrafish. Despite being a non-mammalian animal, the zebrafish model has proven its potential in recapitulating the phenotypes of many different human genetic disorders. This review will focus on recent advances in the modeling of neurodevelopmental disorders in zebrafish, covering aspects from early brain development to techniques used for modulating gene expression, as well as how to best characterize the resulting phenotypes. We also review other existing models of neurodevelopmental disorders, and the current efforts in developing and testing compounds with potential therapeutic value.

Zebrafish as a Model of Neurodevelopmental Disorders

“…Zebrafish are further suitable for studying NDDs (Dorsemans A-C et al, 2017) due to high neuroplasticity, enabling the analyses of multiple neuronal adaptations ( Ghosh S and Hui SP, 2016) and their behavioral (e.g., sociality or emotionality) correlates (Teles MC et al, 2016) controlled by relatively well-defined circuits (Perathoner S et al, 2016). The growing number of zebrafish genes whose orthologs have been implicated in human NDDs (Fontana BD,Franscescon F,Rosemberg DB,Norton WHJ,Kalueff AV and Parker MO, 2019;Vaz R et al, 2019) supports the value of this organism for developing new CNS targets. Finally, important advantages of zebrafish models of NDDs (over mammals) include their high-throughput potential (Jordi J et al, 2018) and better compliance, as lower vertebrates, with bioethical animal experimentation and 3R principles ( .…”

Clozapine-induced transcriptional changes in the zebrafish brain

“…Zebrafish are non-mammalian, with a less complex central nervous system (CNS) than humans, although they show similar patterns of brain development and conserved brain structure with mammals. 15,66 Furthermore, there is a high degree of genetic orthologuey to human, with >70% of the genome conserved. 16 Second, our analyses were performed on bulk brain tissue comprising a mix of brain regions and different neural celltypes.…”

Behavioral effects of developmental exposure to JWH-018 in wild type and disrupted in schizophrenia 1 (disc1) mutant zebrafish

“…In our study, exposure to JWH-018 started at 24 hours post fertilization, a period in which the main zebrafish brain structures (i.e. forebrain, midbrain, and hindbrain) are formed, but finer structures are still to be defined [48]. It is possible that exposures at such early ages lead to persistent adaptive changes in gene expression and neurotransmission different from the adaptive mechanisms happening during other developmental periods -such as adolescence-, which in turn may lead to different alterations in the anxiety-like responses in zebrafish in later life.…”