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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Vydané v:	Progress in neuro-psychopharmacology & biological psychiatry Ročník 143; s. 111528
Hlavní autori:	Li, Wen, Zhang, Xiaocong, Niu, Xiaoyu, Qin, Nan, Kang, Lulu, Wang, Kai, Wang, Mingyong
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England Elsevier Inc 20.12.2025
Predmet:	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
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Abstract	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.
AbstractList	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. 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. 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.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.
ArticleNumber	111528
Author	Kang, Lulu Niu, Xiaoyu Wang, Mingyong Zhang, Xiaocong Wang, Kai Li, Wen Qin, Nan
Author_xml	– sequence: 1 givenname: Wen surname: Li fullname: Li, Wen organization: Department of Pediatrics, 1st Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan Province, China – sequence: 2 givenname: Xiaocong surname: Zhang fullname: Zhang, Xiaocong organization: Department of Pediatrics, 1st Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan Province, China – sequence: 3 givenname: Xiaoyu surname: Niu fullname: Niu, Xiaoyu organization: Department of Pediatrics, 1st Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan Province, China – sequence: 4 givenname: Nan surname: Qin fullname: Qin, Nan organization: Department of Pediatrics, 1st Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan Province, China – sequence: 5 givenname: Lulu surname: Kang fullname: Kang, Lulu organization: Department of Pediatrics, 1st Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan Province, China – sequence: 6 givenname: Kai surname: Wang fullname: Wang, Kai email: wwwkkk8815@163.com organization: Department of Pediatrics, 1st Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan Province, China – sequence: 7 givenname: Mingyong surname: Wang fullname: Wang, Mingyong email: maihe123456789@163.com organization: Murui Biological Technology Co., Ltd., Suzhou Industrial Park, Suzhou, China
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Keywords	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
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Snippet	Dopamine plays a crucial role in regulating movement, motivation, attention, and emotions. Disruptions in dopamine metabolism have been linked to various...
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SubjectTerms	Autism spectrum disorder Behavioural analysis Dopamine dysfunction slc6a3 Zebrafish model
Title	Dopamine disruption and autism phenotypes in slc6a3−/− zebrafish: Behavioural and molecular insights
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