Dopamine disruption and autism phenotypes in slc6a3−/− zebrafish: Behavioural and molecular insights

Dopamine plays a crucial role in regulating movement, motivation, attention, and emotions. Disruptions in dopamine metabolism have been linked to various psychiatric disorders, including autism spectrum disorder (ASD). In this study, we generated an slc6a3 knockout zebrafish model using the CRISPR-C...

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Published in:Progress in neuro-psychopharmacology & biological psychiatry Vol. 143; p. 111528
Main Authors: Li, Wen, Zhang, Xiaocong, Niu, Xiaoyu, Qin, Nan, Kang, Lulu, Wang, Kai, Wang, Mingyong
Format: Journal Article
Language:English
Published: England Elsevier Inc 20.12.2025
Subjects:
Autism spectrum disorder
Behavioural analysis
Dopamine dysfunction
slc6a3
Zebrafish model
AB
mpf
slc6a3
Behavioural analysis
ARRIVE
KO
Zebrafish model
HPLC-ECD
IHC
Autism spectrum disorder
SD
RNA-seq
TH
ANOVA
Dopamine dysfunction
IACUC
qPCR
SEM
dpf
DA
ELISA
ISH
ISSN:0278-5846, 1878-4216, 1878-4216
Online Access:Get full text
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Summary:Dopamine plays a crucial role in regulating movement, motivation, attention, and emotions. Disruptions in dopamine metabolism have been linked to various psychiatric disorders, including autism spectrum disorder (ASD). In this study, we generated an slc6a3 knockout zebrafish model using the CRISPR-Cas9 system to investigate the relationship between dopamine dysfunction and autism. Our results revealed that slc6a3 knockout significantly reduced dopamine levels, leading to impaired dopamine synthesis, transport, and metabolism. Behavioural analysis demonstrated that slc6a3−/− zebrafish exhibited decreased motor activity, increased anxiety-like behaviour, and autism-related symptoms, such as impaired social ability and “digging” behaviour. Pharmacological intervention with risperidone and clozapine improved motor function, social interaction, and anxiety levels, with risperidone showing superior effects. Transcriptomic analysis identified significant changes in several nervous system-related genes in slc6a3−/− zebrafish, suggesting that these gene alterations may contribute to the observed behavioural abnormalities. Our study highlights the crucial role of dopamine dysfunction in autism and establishes slc6a3−/− zebrafish as a valuable model for studying autism and screening potential therapeutic drugs. •Generation of a CRISPR/Cas9-based zebrafish slc6a3 knockout model mimicking dopamine transporter deficiency.•Comprehensive behavioural phenotyping across developmental stages revealed locomotor, anxiety-like, and social interaction deficits.•Pharmacological rescue with risperidone and clozapine demonstrated predictive validity and differential efficacy in the zebrafish model.•Molecular and transcriptomic analyses identified dopaminergic pathway alterations and potential compensatory mechanisms.•Zebrafish slc6a3 mutants provide a translational platform for investigating dopamine-related neurodevelopmental disorders and drug screening.
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ISSN:0278-5846
1878-4216
1878-4216
DOI:10.1016/j.pnpbp.2025.111528