Function Over Form: Modeling Groups of Inherited Neurological Conditions in Zebrafish

Abstract

Zebrafish are a unique cell to behavior model for studying the basic biology of human inherited neurological conditions. Conserved vertebrate genetics and optical transparency provide in vivo access to the developing nervous system as well as high-throughput approaches for drug screens. Here we review zebrafish modeling for two broad groups of inherited conditions that each share genetic and molecular pathways and overlap phenotypically: neurodevelopmental disorders such as Autism Spectrum Disorders (ASD), Intellectual Disability (ID) and Schizophrenia (SCZ), and neurodegenerative diseases, such as Cerebellar Ataxia (CATX), Hereditary Spastic Paraplegia (HSP) and Charcot-Marie Tooth Disease (CMT). We also conduct a small meta-analysis of zebrafish orthologs of high confidence neurodevelopmental disorder and neurodegenerative disease genes by looking at duplication rates and relative protein sizes. In the past zebrafish genetic models of these neurodevelopmental disorders and neurodegenerative diseases have provided insight into cellular, circuit and behavioral level mechanisms contributing to these conditions. Moving forward, advances in genetic manipulation, live imaging of neuronal activity and automated high-throughput molecular screening promise to help delineate the mechanistic relationships between different types of neurological conditions and accelerate discovery of therapeutic strategies.

The zebrafish as a promising tool for modeling human brain disorders: A review based upon an IBNS Symposium

“…In light of concerns that MO injections cause unwanted and poorly understood side effects, which often include alterations to head size, neuronal development, and perturbations of motor neuron function, most zebrafish studies of ASD using MOs should now be interpreted with great caution (Lawson, 2016 (Eisen and Smith, 2008), including 1) phenotypic rescue by co-injecting mRNA, 2) using two independent MOs targeting the same gene, and 3) confirmation by comparison to a mutant in the same gene. Perhaps the tendency of ASD-risk genes to be unusually large in both humans and zebrafish (King et al, 2013;Kozol et al, 2016) has precluded easy demonstration of morphant rescue with functional mRNA, but this only emphasizes the need for confirmation of morphant ASD phenotypes with genetic mutations. Shams et al…”

“…Many of the large ASD genes undergo complex alternative splicing, so mutants must be carefully evaluated for true loss of function. Intriguingly, some 50-60% of ASD genes are duplicated in zebrafish (compared to roughly 20% across the mammalian genome), which may require the targeting of each copy to create a loss of function ASD gene model (Kozol et al, 2016).…”

Genetic compensation in a stable slc25a46 mutant zebrafish: A case for using F0 CRISPR mutagenesis to study phenotypes caused by inherited disease

“…Recently, reports of discrepancies between knockdown and mutant phenotypes have increased, many of which were observed in zebrafish [20][21][22][23][24][25]. Zebrafish are a versatile convenient vertebrate model system with many advantages for reverse genetics, such as simplicity of genetic manipulation, fast generation times of large numbers of progeny, and optical transparency suitable for live imaging [26]. Thus, absence of stable mutant phenotypes and inconsistencies with the knockdown morpholino-induced phenotypes have raised concerns in the functional genetics field that is aimed at understanding disease symptom etiology.…”

Zebrafish Models of Neurodevelopmental Disorders: Past, Present, and Future

“…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). For example, 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.…”