Abstract
Clozapine is an atypical antipsychotic medication that is used to treat schizophrenia patients who are resistant to other antipsychotic drugs. The molecular mechanisms mediating the effects of clozapine are not well understood and its use is often associated with severe side-effects. In this study, we exposed groups of wild-type zebrafish to two doses of clozapine (‘low’ (20 µg/L) and ‘high’ (70 µg/L)) over a 72-h period, observing dose-dependent effects on behaviour. Using RNA sequencing (RNA-seq) we identified multiple genes differentially expressed in the zebrafish brain following exposure to clozapine. Network analysis identified co-expression modules characterised by striking changes in module connectivity in response to clozapine, and these were enriched for regulatory pathways relevant to the etiology of schizophrenia. Our study highlights the utility of zebrafish as a model for assessing the molecular consequences of antipsychotic medications and identifies genomic networks potentially involved in schizophrenia.
Highlights
Schizophrenia is a severe psychiatric disorder affecting more than 21 million people worldwide and contributing significantly to the global burden of disease.[1,2] It is characterised by symptoms of social isolation, apathy and lack of drive, interference with thought processes, hallucinations and delusions.[3]
We assessed individual fish to analyse changes in behaviour associated with clozapine exposure
Total RNA was isolated from brain tissue and used for messenger RNA-sequencing (RNA-seq) for samples exposed to water control (n = 16), dimethyl sulfoxide (DMSO) vehicle (n = 16), ‘low’’ clozapine exposure (n = 16) and ‘high’ clozapine exposure (n = 16)
Summary
Schizophrenia is a severe psychiatric disorder affecting more than 21 million people worldwide and contributing significantly to the global burden of disease.[1,2] It is characterised by symptoms of social isolation, apathy and lack of drive, interference with thought processes, hallucinations and delusions.[3] There is no cure for schizophrenia; current treatments act by reversing the symptoms of disease rather than preventing the development of underlying pathology. Patients prescribed clozapine need to be carefully monitored for the development of serious blood disorders such as agranulocytosis.[9]
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