Sex-specific Neurological Dysregulation May Underpin Distinctly Different Male and Female Behavioural Phenotypes in A Zebrafish Model of Autism Spectrum Disorder

Behavioral and brain functions : BBF  ·  2026

Lesha Pretorius; Tamera Moodley; Carine Smith;

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ABSTRACT

Although distinctly different phenotypes of male and female autism spectrum disorder (ASD) have been long proposed, mechanistic insights are relatively lacking. Added complexities are that human ASD neurological data has been predominantly generated in males, while behavioural observations are influenced by social norms. Using a preclinical in vivo model of idiopathic ASD, the current study may contribute to our understanding of the differences between the male and female ASD phenotype. Briefly, ASD-like phenotype was induced in zebrafish embryos via valproate immersion. After confirmation of the larval phenotype, zebrafish were raised to adulthood to allow for sex-specific assessments. Adult behaviour was assessed in terms of anxiety (novel tank test), social interaction (social preference test) and aggression (mirror biting test). Behavioural data was interpreted in the context of whole brain proteome profiles obtained by untargeted proteomics. Differential protein expression analyses were performed using the Benjamini-Hochberg false discovery rate (significance at < 5%). In addition, main effects of ASD-like phenotype and sex were evaluated for specific neurotransmitter proteins. Behavioural data generally illustrated convergence of sexes in the ASD-like groups. For example, ASD-like males demonstrated a similar but exaggerated anxiety-like outcome, while ASD-like females exhibited behavioural responses more like control and ASD-like males within the social preference assay. Current data do not support aggressive behaviour as a hallmark of ASD in this model. In terms of neurotransmission profiles, significant sex-specific dysregulation was observed within the glutamatergic, GABAergic and dopaminergic systems. For example, greater excitation/inhibition imbalance was exhibited in ASD-like males vs. ASD-like females. Due to low abundance, data on the serotonergic system is less conclusive. Despite similar behavioural profiles, distinct neurotransmitter mechanisms elucidated may potentially warrant the consideration of sex-specific therapeutic targets in the ASD context.

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