Journal article
Towards modelling mental disorders in zebrafish. Neurexins severely modulate anxiety, affiliative social behaviour and aggression
Molecular Psychiatry, Vol.Advanced access
26-Jun-2026
PMID: 42362769
Abstract
Neurexin (nrxn) genes encode synaptic cell-adhesion molecules that have been repetitively associated with neurodevelopmental and mental disorders. While the zebrafish animal model offers tremendous advantages for dissecting neural development/function, no complete loss-of-function (LOF) nrxn zebrafish models are currently available. In this study, we generated the first collection of zebrafish knockout lines for each nrxn gene, with mutations ranging from transmembrane domain- to full genomic locus-deletions. Surprisingly, all homozygous lines developed normally, presenting no gross neurodevelopmental or obvious early behavioural abnormalities. However, this absence of early phenotypes translated into profound, paralog-specific behavioural alterations emerging during later developmental stages. All neurexin knockouts affected mating behaviour, complicating the generation and maintenance of homozygous lines. Except for this shared behavioural alteration, nrxn1, but not nrxn2 or nrxn3, led to marked changes in affiliative social behaviour and aggression. In contrast, nrxn2 mutants exhibited severe anxiety-like behaviours, including bottom-dwelling and repetitive freezing/seizure events. Strikingly, nrxn1 full-locus deletion mutants showed opposing behaviour, spending most of their time near the surface. The two also displayed opposite responses to open/closed field transitions; confinement alleviated nrxn2 anxiety but enhanced nrxn1 surface-dwelling. Meanwhile, nrxn3 mutants behaved normally in all our initial tests. In summary, our study introduces a complete set of zebrafish mutants covering the whole nrxn gene family, presenting striking adult behavioural alterations despite the absence of noticeable early defects; echoing the delayed onset of human psychiatric disorders such as schizophrenia. This work confirms the value of zebrafish to study mental disorders and unlock a novel platform to unravel the pathogenic contribution of neurexins and associated subtle neurodevelopmental changes/timing that drive the emergence of mental illnesses.Neurexin (nrxn) genes encode synaptic cell-adhesion molecules that have been repetitively associated with neurodevelopmental and mental disorders. While the zebrafish animal model offers tremendous advantages for dissecting neural development/function, no complete loss-of-function (LOF) nrxn zebrafish models are currently available. In this study, we generated the first collection of zebrafish knockout lines for each nrxn gene, with mutations ranging from transmembrane domain- to full genomic locus-deletions. Surprisingly, all homozygous lines developed normally, presenting no gross neurodevelopmental or obvious early behavioural abnormalities. However, this absence of early phenotypes translated into profound, paralog-specific behavioural alterations emerging during later developmental stages. All neurexin knockouts affected mating behaviour, complicating the generation and maintenance of homozygous lines. Except for this shared behavioural alteration, nrxn1, but not nrxn2 or nrxn3, led to marked changes in affiliative social behaviour and aggression. In contrast, nrxn2 mutants exhibited severe anxiety-like behaviours, including bottom-dwelling and repetitive freezing/seizure events. Strikingly, nrxn1 full-locus deletion mutants showed opposing behaviour, spending most of their time near the surface. The two also displayed opposite responses to open/closed field transitions; confinement alleviated nrxn2 anxiety but enhanced nrxn1 surface-dwelling. Meanwhile, nrxn3 mutants behaved normally in all our initial tests. In summary, our study introduces a complete set of zebrafish mutants covering the whole nrxn gene family, presenting striking adult behavioural alterations despite the absence of noticeable early defects; echoing the delayed onset of human psychiatric disorders such as schizophrenia. This work confirms the value of zebrafish to study mental disorders and unlock a novel platform to unravel the pathogenic contribution of neurexins and associated subtle neurodevelopmental changes/timing that drive the emergence of mental illnesses.
Details
- Title
- Towards modelling mental disorders in zebrafish. Neurexins severely modulate anxiety, affiliative social behaviour and aggression
- Authors
- Q Nguyen - Griffith UniversityF Guo - Griffith UniversityJ Das - Griffith UniversityO Hatzimanolis - Griffith UniversityB Mowry - The University of QueenslandAlexandre S Cristino - Griffith UniversityJ Giacomotto - University of the Sunshine Coast
- Publication details
- Molecular Psychiatry, Vol.Advanced access
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/s41380-026-03721-1
- ISSN
- 1476-5578
- PMID
- 42362769
- Copyright note
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Grants
- Grant note
- Rebecca Cooper Medical Research Project Grant No PG2019405
- Organisation Unit
- Thompson Institute
- Language
- English
- Record Identifier
- 991243598702621
- Output Type
- Journal article
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