Abstract
Zebrafish are increasingly being utilized as a model system to investigate the function of the growing list of risk genes associated with neurodevelopmental disorders. This is due in large part to the unique features of zebrafish that make them an optimal system for this purpose, including rapid, external development of transparent embryos, which enable the direct visualization of the developing nervous system during early stages, large progenies, which provide considerable tractability for performing high-throughput pharmacological screens to identify small molecule suppressors of simple behavioral phenotypes, and ease of genetic manipulation, which has been greatly facilitated by the advent of CRISPR/Cas9 gene editing technologies. This review article focuses on studies that have harnessed these advantages of the zebrafish system for the functional analysis of genes that are strongly associated with the following neurodevelopmental disorders: autism spectrum disorders (ASD), epilepsy, intellectual disability (ID) and schizophrenia. We focus primarily on studies describing early morphological and behavioral phenotypes during embryonic and larval stages resulting from loss of risk gene function. We highlight insights into basic mechanisms of risk gene function gained from these studies as well as limitations of studies to date. Finally, we discuss advances in in vivo neural circuit imaging in zebrafish, which promise to transform research using the zebrafish model by illuminating novel circuit-level mechanisms with relevance to neurodevelopmental disorders.
Highlights
In recent years, there has been growing interest in the use of zebrafish as a model system for the functional analysis of genes in neurodevelopmental disorders, which are a group of disorders characterized by alterations in behavior, cognition, communication, and/or motor function during development (American Psychiatric Association, 2013)
While zebrafish have been used to study other neurodevelopmental disorders, including attentiondeficit/hyperactivity disorder (ADHD; Lange et al, 2012a,b), Bardet-Biedl syndrome (BBS; Zaghloul et al, 2010; Heon et al, 2016; Lindstrand et al, 2016), and maple syrup urine disease (MSUD; Friedrich et al, 2012), we focus on autism spectrum disorders (ASD), epilepsy, intellectual disability (ID) and schizophrenia, which have been the subject of most zebrafish studies to date and highlight the advantages of this system for the functional analysis of risk genes
Zebrafish have critical advantages as a model system for investigating the function of genes associated with neurodevelopmental disorders
Summary
There has been growing interest in the use of zebrafish as a model system for the functional analysis of genes in neurodevelopmental disorders, which are a group of disorders characterized by alterations in behavior, cognition, communication, and/or motor function during development (American Psychiatric Association, 2013). This is due in large part to the unique features of this system, which offer distinct advantages over more traditional model systems (McCammon and Sive, 2015; Ijaz and Hoffman, 2016; Kozol et al, 2016). Zebrafish have transparent embryos that develop externally and rapidly, allowing for the direct visualization of neurodevelopmental processes and neural activity in an intact, functioning nervous system. Zebrafish are highly tractable and produce large progenies, which facilitate the conduct of high-throughput pharmacological screens at a scale that would not be feasible in rodent models
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