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
BACKGROUND
Autism spectrum disorder (ASD) lacks disease-modifying therapies. Gene therapy offers a promising avenue to target the underlying molecular causes of ASD, particularly in monogenic or syndromic forms where single-gene mutations play a central role.
METHODS
A scoping review was conducted following the PRISMA-ScR framework. We searched PubMed, Scopus, Web of Science, PsycINFO, and the Cochrane Library (2000-July 2025), with the last search completed in July 2025. Eligible studies included preclinical or translational investigations involving gene-therapy modalities (e.g., AAV vectors, ASOs, CRISPR-based editing) targeting high-confidence ASD-linked genes; non-gene-therapy studies, unrelated conditions, reviews, and non-English papers were excluded. Data were charted using a standardized extraction form and synthesized descriptively across two evidence streams. Stream 1 evaluated preclinical studies of gene therapy, while Stream 2 examined translational advances and ethical considerations.
RESULTS
Twenty-one preclinical studies were identified in Stream 1, focusing on genes such as UBE3A, MECP2, FMR1, SHANK3/2, SCN2A, and SYNGAP1. Most demonstrated molecular correction and improvements in synaptic, electrophysiological, and behavioral outcomes, with therapeutic effects observed from early developmental to adult timepoints. Stream 2 synthesized 12 studies highlighting translational challenges, including delivery innovations (e.g., engineered viral capsids, nanoparticles), safety concerns (immune responses, dose-dependent toxicities), and ethical considerations (pediatric consent, neurodiversity perspectives, equity in access). Limitations include heterogeneity across models, reliance on rodent studies, and absence of completed human clinical trials.
CONCLUSIONS
Gene therapy for ASD shows considerable promise but faces significant translational and ethical hurdles. 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
The heterogeneity in both the neurobiological mechanisms and the phenotypic presentations of autism spectrum disorder (ASD) poses a major challenge to clinical and translational research. Alterations in functional connectivity (FC) have been associated with ASD, yet it remains unclear whether and how divergent brain network properties may account for individual differences across ASD-related symptomatology and behaviors. We applied source-level reconstruction to rest-like non-task-related high-density EEG data in a cohort of 104 young children (38 with ASD) to identify global and local alterations of cortical network connectivity. We subsequently used regularized canonical correlation analysis (rCCA) to characterize specific FC patterns linked to variation in cognitive, social and sensory dimensions derived from standard clinical instruments. We found increased low-frequency FC in frontotemporal cross-hemispheric networks and lateral-occipital regions of young ASD children versus healthy peers. RCCA revealed three distinct FC patterns in recurrent ASD-related networks, each contributing to predict individual differences in cognitive, social and sensory features. These linked FC-behavior dimensions may shed light on atypical brain network topology associated with specific phenotypic manifestations of ASD, which might implicate unique underlying neurobiological mechanisms.
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
