A critical review of zebrafish schizophrenia models: Time for validation?

Gaweł, Kinga; Banono, Nancy Saana; Michalak, Agnieszka; Esguerra, Camila V.

doi:10.1016/j.neubiorev.2019.08.001

Cited by 34 publications

(31 citation statements)

References 397 publications

(852 reference statements)

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“…In conclusion, different zebrafish genetic models of epilepsy and to a lesser extent, SCZ, have emerged within the last 5 years (for comprehensive reviews see [106,107]). Although the zebrafish brain is less complex than the mammalian one, fish are very sensitive to neuroactive compounds and their behavioural responses are easily tracked in 48-well plates.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?

et al. 2020

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Persons with certain single nucleotide polymorphisms (SNPs) in the CACNA1D gene (encoding voltage-gated calcium channel subunit alpha 1-D) have increased risk of developing neuropsychiatric disorders such as bipolar, schizophrenia and autism. The molecular consequences of SNPs on gene expression and protein function are not well understood. Thus, the use of animal models to determine genotype-phenotype correlations is critical to understanding disease pathogenesis. Here, we describe the behavioural changes in larval zebrafish carrying an essential splice site mutation (sa17298) in cacna1da. Heterozygous mutation resulted in 50% reduction of splice variants 201 and 202 (haploinsufficiency), while homozygosity increased transcript levels of variant 201 above wild type (WT; gain-of-function, GOF). Due to low homozygote viability, we focused primarily on performing the phenotypic analysis on heterozygotes. Indeed, cacna1dasa17298/WT larvae displayed hyperlocomotion—a behaviour characterised in zebrafish as a surrogate phenotype for epilepsy, anxiety or psychosis-like behaviour. Follow-up tests ruled out anxiety or seizures, however, as neither thigmotaxis defects nor epileptiform-like discharges in larval brains were observed. We therefore focused on testing for potential “psychosis-like” behaviour by assaying cacna1dasa17298/WT larval locomotor activity under constant light, during light-dark transition and in startle response to dark flashes. Furthermore, exposure of larvae to the antipsychotics, risperidone and haloperidol reversed cacna1da-induced hyperactivity to WT levels while valproate decreased but did not reverse hyperactivity. Together, these findings demonstrate that cacna1da haploinsufficiency induces behaviours in larval zebrafish analogous to those observed in rodent models of psychosis. Future studies on homozygous mutants will determine how cacna1d GOF alters behaviour in this context.

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Section: Discussionmentioning

confidence: 99%

Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?

et al. 2020

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“…Schizophrenia is a complex psychiatric disorder thought to arise from abnormalities during development of the brain; however, its exact causes are unknown ( Weinberger, 1987 ). Pharmacological and genetic zebrafish models have been developed to help unravel the etiology of the disease ( Gawel et al, 2019 ). It will be interesting to see whether network scoring with the transcriptomes of these models might help identify not only the affected neurodevelopmental processes but also an effective treatment for reversing these changes.…”

Section: Discussionmentioning

confidence: 99%

Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish

Talikka

Gubian

et al. 2021

Front. Genet.

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Adverse outcomes that result from chemical toxicity are rarely caused by dysregulation of individual proteins; rather, they are often caused by system-level perturbations in networks of molecular events. To fully understand the mechanisms of toxicity, it is necessary to recognize the interactions of molecules, pathways, and biological processes within these networks. The developing brain is a prime example of an extremely complex network, which makes developmental neurotoxicity one of the most challenging areas in toxicology. We have developed a systems toxicology method that uses a computable biological network to represent molecular interactions in the developing brain of zebrafish larvae. The network is curated from scientific literature and describes interactions between biological processes, signaling pathways, and adverse outcomes associated with neurotoxicity. This allows us to identify important signaling hubs, pathway interactions, and emergent adverse outcomes, providing a more complete understanding of neurotoxicity. Here, we describe the construction of a zebrafish developmental neurotoxicity network and its validation by integration with publicly available neurotoxicity-related transcriptomic datasets. Our network analysis identified consistent regulation of tumor suppressors p53 and retinoblastoma 1 (Rb1) as well as the oncogene Krüppel-like factor (Klf8) in response to chemically induced developmental neurotoxicity. The developed network can be used to interpret transcriptomic data in a neurotoxicological context.

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“…Interestingly, PFNA exposure also caused males to attack their reflection more, indicating more aggression, while PFOS exposure decreased attacks ( Table 2 A,B) [ 48 ]. Importantly, while the findings should be confirmed in mammalian models, it is worth noting that schizophrenia risk genes are well conserved across taxa and fish models have been highly useful in the study of chemically induced phenotypes relevant to psychiatric disorders [ 60 , 61 , 62 ]. Thus, these data indicate that PFAS could be causing neurological effects and should be studied further as potentially increasing risk of psychiatric disorders.…”

Section: Vertebrate Species Used To Study Neurotoxicity Of Pfasmentioning

confidence: 99%

Per- and Polyfluoroalkyl Substances (PFAS) Neurotoxicity in Sentinel and Non-Traditional Laboratory Model Systems: Potential Utility in Predicting Adverse Outcomes in Human Health

Foguth

Sepúlveda

Cannon

2020

Toxics

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Per- and polyfluoroalkyl substances (PFAS) are a class of chemicals that were widely used in manufacturing and are now present in the environment throughout the world. It is known that various PFAS are quantifiable in human in blood, but potential adverse health outcomes remain unclear. Sentinel and non-traditional model species are useful to study potential toxicity of PFAS in order to understand the relationship between environmental and human health. Here, we present a critical review of studies on the neurotoxicity of PFAS in sentinel and non-traditional laboratory model systems, including Caenorhabditis elegans (nematode), Dugesia japonica (planarian), Rana pipiens (frogs), Danio rerio and Oryzias melastigma (fish), and Ursus maritimus (polar bears). PFAS have been implicated in developmental neurotoxicity in non-traditional and traditional model systems as well as sentinel species, including effects on neurotransmitter levels, especially acetylcholine and its metabolism. However, further research on the mechanisms of toxicity needs to be conducted to determine if these chemicals are affecting organisms in a similar manner. Overall, findings tend to be similar among the various species, but bioaccumulation may vary, which needs to be taken into account in future studies by quantifying target organ concentrations of PFAS to better compare different species. Furthermore, data on the majority of PFAS is lacking in neurotoxicity testing, and additional studies are needed to corroborate findings thus far.

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A critical review of zebrafish schizophrenia models: Time for validation?

Cited by 34 publications

References 397 publications

Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?

Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?

Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish

Per- and Polyfluoroalkyl Substances (PFAS) Neurotoxicity in Sentinel and Non-Traditional Laboratory Model Systems: Potential Utility in Predicting Adverse Outcomes in Human Health

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