Genetic disruption of leucine rich repeat transmembrane protein 4 like 1 induces a pro-social behavioural phenotype in zebrafish

Hillman, C. S.; Petracco, G.; Fontana, B. D.; Scaia, M. F.; Dalla Vecchia, E.; Wetton, J. H.; Norton, W. H.; Parker, M. O.; Reichmann, F.

doi:10.1101/2025.05.12.653402

bioRxiv · 10.1101/2025.05.12.653402

Genetic disruption of leucine rich repeat transmembrane protein 4 like 1 induces a pro-social behavioural phenotype in zebrafish

Hillman, C. S.·Petracco, G.·Fontana, B. D.·Scaia, M. F.·Dalla Vecchia, E.·Wetton, J. H.·Norton, W. H.·Parker, M. O.·Reichmann, F.

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Abstract

BackgroundSocial behaviour encompasses the wide range of interactions that occur between members of the same species. In humans, disruptions in social behaviour are characteristic of many neuropsychiatric disorders, where both genetic risk factors and synaptic dysfunctions can contribute to the phenotype. Among the genes implicated in synaptic regulation, the synaptic adhesion protein leucine-rich repeat transmembrane protein 4 (LRRTM4) has been identified as a key player in maintaining synaptic function and neuronal circuit integrity. Despite its established role in the nervous system, the potential involvement of LRRTM4 in modulating social behaviour and its contribution to social deficits has yet to be explored. MethodsIn the current study, we used zebrafish to study how genetic deletion of lrrtm4l1, a zebrafish orthologue of LRRTM4, affects sociality. For this, the social behaviour of homozygous lrrtm4l1 knockout (KO) zebrafish was analysed in multiple behavioural assays and the brain transcriptome of mutant animals was investigated by RNAseq. ResultsKO zebrafish displayed a pro-social phenotype in multiple behavioural assays. Groups of lrrtm4l1 KO zebrafish formed more cohesive shoals and KO individuals spent more time in the vicinity of conspecifics during a social interaction test. They were also less aggressive and in contrast to wild-type zebrafish did not differentiate in their interactions with known and unknown groups of fish. Neurotranscriptomic analysis revealed 560 differentially expressed genes including changes in glutamatergic neurotransmitter signalling, tryptophan- kynurenine metabolism and synaptic plasticity. ConclusionThese findings suggest that lrrtm4l1 is an important regulator of social behaviour in zebrafish. In a translational perspective, LRRTM4 is a promising potential therapeutic target that warrants further investigation in the framework of neuropsychiatric conditions characterized by major social impairments.

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Hillman, C. S., Petracco, G., Fontana, B. D., Scaia, M. F., Dalla Vecchia, E., Wetton, J. H., Norton, W. H., Parker, M. O., Reichmann, F.. 2025-05-14. Genetic disruption of leucine rich repeat transmembrane protein 4 like 1 induces a pro-social behavioural phenotype in zebrafish. https://doi.org/10.1101/2025.05.12.653402

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