Animal models of autism spectrum disorder: Bridging biology to behaviour

Abstract

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.