Animal models of autism spectrum disorder: Bridging biology to behaviour.
Pilar Martinez OlondoAlban de Kerchove d'Exaerde
Aug 2026· Developmental Medicine & Child Neurology· 0 citations· 83 references
Medicine
TL;DR
The framework used to evaluate the relevance of animal models-construct, face, and predictive validity-is outlined and the behavioural paradigms used to assess core ASD-related domains in rodents are summarized, including social interaction and communication, restricted and repetitive behaviours, and cognitive flexibility.
Abstract
The prevalence of autism spectrum disorder (ASD) has risen over the decades, reflecting improved awareness and evolving diagnostic practice. ASD is characterized by clinical and biological heterogeneity, with diverse genetic and environmental risk factors converging on disruption of synaptic function, circuits, and behaviour. This complexity limits mechanistic inference from human studies and underscores the importance of animal models for establishing causal relationships between risk mechanisms and ASD-relevant phenotypes. In this review, we outline the framework used to evaluate the relevance of animal models-construct, face, and predictive validity-and summarize the behavioural paradigms used to assess core ASD-related domains in rodents, including social interaction and communication, restricted and repetitive behaviours, and cognitive flexibility. We then examine mouse models of ASD, encompassing genetically engineered lines and inbred and idiopathic strains, discussing their mechanistic contributions, limitations, and sources of phenotypic variability. In addition, we briefly review environmental models and complementary animal species, which provide insights into distinct aspects of ASD biology. Collectively, the available models reveal convergent molecular and circuit mechanisms underlying ASD-related phenotypes. When interpreted within a framework and supported by standardized behavioural and physiological approaches, these models constitute a powerful platform for elucidating ASD pathophysiology and for guiding the preclinical development of targeted therapeutic strategies.
Autism spectrum disorder (ASD) exhibits pronounced heterogeneity across genetic, neurobiological, and clinical phenotypic levels, posing substantial challenges for mechanistic elucidation and clinical translation. This review synthesizes advances in data-driven approaches to parsing ASD heterogeneity and centers the discussion on three complementary strata: neural, behavioral, and transdiagnostic subtypes. At the neuroimaging level, studies leveraging features such as functional connectivity and brain structure have consistently identified two core neurosubtypes characterized by increased and decreased neural activity, respectively. These neurosubtypes differ in time-varying dynamics, spatial architecture, and network hierarchy, and they are closely associated with specific symptom dimensions and cognitive functions. At the behavioral level, data-driven methods delineate phenotypes along axes of severity and functional impairment, and further reveal their links to neural circuits. Transdiagnostic investigations indicate that ASD and frequently co-occurring disorders share neurobiological substrates and cognitive endophenotypes. Collectively, these findings argue against a simple one-to-one correspondence between behavioral and neural subtypes; instead, the evidence is more consistent with multi-to-one, one-to-many, or many-to-many mappings that converge on the overall functional impairment. Notwithstanding this progress, major challenges remain, including sample heterogeneity, methodological inconsistency, and the integration of categorical and dimensional models. Future research should prioritize large samples, multi-site collaboration, longitudinal designs, and transdiagnostic frameworks, coupled with reverse validation via intervention response, to build robust evidence for mechanism-informed individualized assessment and intervention in ASD.
Xingke Wang, Zhou Zhang, Shuang Li et al.· Translational Psychiatry· 0 citations
Gene therapy for ASD shows considerable promise but faces significant translational and ethical hurdles and standardized study designs, comprehensive safety evaluation, and transparent stakeholder engagement will be critical for developing responsible and effective clinical applications.
Ali Naderi Malek, Amir Hossein Rasoli Jokar, Patricia Prelock· Neuropsychobiology· 0 citations
Autism spectrum disorder is a heterogeneous condition marked by social communication difficulties and restricted/repetitive behaviors. Although major progress has been made over the past two decades in understanding its genetics and molecular mechanisms, effective treatments remain limited. Report from the 2021 Lancet Commission on autism recommends that research should focus on improving quality of life through personalized assessment and intervention. Due to its heterogeneity, multiple treatment strategies will likely be needed. For some individuals, especially those with severe syndromic autism, gene therapy may offer future therapeutic options. To match patient subgroups to treatments, both "mutation clustering to treatment" forward approach and "treatment to disease subgroup" reverse approach can be used. Building a broad treatment portfolio will take time, but even incremental advances would be meaningful. Principles of neural plasticity, such as early intervention and repeated practice, may also enhance outcomes alone or alongside other therapies.
Xiang Yu· Current Opinion in Neurobiol...· 0 citations
RCCA revealed three distinct FC patterns in recurrent ASD-related networks, each contributing to predict individual differences in cognitive, social and sensory features, which may shed light on atypical brain network topology associated with specific phenotypic manifestations of ASD.
B. Rodríguez-Herreros, A. Mheich, J. A. Osório et al.· Autism Research· 0 citations
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
Despite similar behavioural profiles, distinct neurotransmitter mechanisms elucidated may potentially warrant the consideration of sex-specific therapeutic targets in the ASD context.
L. Pretorius, Tamera Moodley, Carine Smith· Behavioral and Brain Functio...· 0 citations
A narrative review of papers published between 1 January 2015 and 16 February 2026 that were pertinent to comorbidity and autism finds how the variable risk of comorbidity mimics the heterogeneity present in autism, thus inviting further investigations.
E. Dando, Juergen Hahn, D. Geier et al.· Healthcare· 0 citations
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