Read, E. (2026). Genetic and behavioural modelling of schizophrenia in the zebrafish [Doctoral dissertation, King's College London]. King's College London Research Portal.
Abstract
Schizophrenia is a severe psychological disorder with an approximate lifetime risk between 0.3% and 0.7%. Current treatments are ineSective at addressing the wide array of symptoms that schizophrenic patients experience, and thus, it is important to explore alternative treatment targets. Zebrafish are an emerging approach for modelling schizophrenia and other neurodevelopmental disorders. This thesis presents data showing the establishment of a high- throughput behavioural pipeline to assess candidate risk genes for schizophrenia in zebrafish models.
Three candidate genes based on human GWAS data were modelled using three diSerent strategies: knock-in of a schizophrenia-specific missense mutation, full knockout and F0 CRISPants. Mutant behaviours were tested in a custom-designed and drug-validated high- throughput behaviour pipeline. This pipeline was developed specifically for the phenotyping of schizophrenia zebrafish larvae by encompassing a variety of behaviour assays that link closely to schizophrenia-relevant endophenotypes. Two juvenile age assays were also used to investigate cognitive/negative schizophrenia symptoms of memory impairment and reduced sociability. Results from all the assays were then summarised in a behavioural barcode for each candidate.
A spectrum of phenotypes was observed that demonstrated how high-throughput pipelines facilitate the emergence of behaviour fingerprints and indicate associated dysfunctional pathways. For example, zdhhc5a/b mutants displayed clear sensory impairments in response to environmental stimuli, as well as aberrant patterns of exploration. This links clearly to the strong expression of both genes in brain regions closely connected to sensory integration and cognitive function. In addition, knocking out tenm4 induced a working memory phenotype in juvenile animals, which correlates well with the high expression of Tenm4 RNA in the pallium. A prominent antipsychotic molecule, clozapine, was also trialled in the schizophrenia pipeline to demonstrate the viability of this approach for future small-molecule testing.
In conclusion, this project has elucidated how genetic and behavioural modelling of schizophrenia is highly compatible with the use of zebrafish as a preclinical model, from the rapid development of complex behaviours and substantial homology of the zebrafish genome to humans, to the propensity for high-throughput behavioural fingerprinting and novel compound screening.
