In a groundbreaking study recently published in Translational Psychiatry, researchers have unveiled compelling insights into the molecular underpinnings of autism-like behaviors in offspring induced by maternal subclinical hypothyroidism (SCH). The investigation, led by Liu, Tao, Sun, and colleagues, advances our understanding of how the Wnt/BDNF signaling pathway mediates neurodevelopmental abnormalities, revealing potential therapeutic targets for autism spectrum disorder (ASD).
Maternal hypothyroidism during pregnancy has long been implicated in adverse neurodevelopmental outcomes in children, but the mechanisms linking maternal thyroid dysfunction to autism have remained elusive. This study bridges that gap by focusing specifically on subclinical hypothyroidism, a condition characterized by subtly reduced thyroid function that often goes undiagnosed yet may exert profound effects on fetal brain development. Using rodent models, the researchers meticulously dissected the behavioral and molecular alterations driven by maternal SCH, illuminating a direct pathway through which thyroid insufficiency cascades into autism-like phenotypes.
At the center of their findings lies the Wnt/BDNF axis, a critical neurodevelopmental signaling pathway known for its roles in neural proliferation, differentiation, and synaptic plasticity. The Wnt proteins regulate a plethora of developmental processes, while brain-derived neurotrophic factor (BDNF) serves as a key neurotrophic factor essential for synaptic maturation and cognitive functions. Disruption in Wnt or BDNF signaling has been consistently linked with neurodevelopmental disorders, making this pathway a focal point for potential interventions.
The study revealed that maternal SCH induced a significant downregulation of Wnt signaling components in the offspring’s brain, particularly in the hippocampus and prefrontal cortex—regions intimately involved in cognition, social behavior, and emotional regulation. Correspondingly, BDNF expression was markedly reduced, suggesting that impaired neurotrophic support compromises synaptic integrity and neural network formation. These molecular changes dovetailed with behavioral abnormalities that mirror core features of autism, including social interaction deficits, increased repetitive behaviors, and heightened anxiety-like responses.
Behavioral assays corroborated the molecular data, with offspring of SCH-affected mothers displaying notable impairments in social novelty preference tests and elevated self-grooming behaviors, both well-established indicators of autism-like phenotypes in rodent models. The anxiety-related phenotype was further substantiated by increased thigmotaxis during open field testing, reflecting heightened stress and altered emotional processing. Importantly, these behavioral features were absent or significantly attenuated in control groups, emphasizing the specificity of the maternal SCH effect.
Underpinning these functional disturbances, synaptic ultrastructure analyses via electron microscopy unveiled pronounced deficits in dendritic spine density and morphology in cortical neurons of SCH offspring. The observed reduction in mature, mushroom-shaped spines points to weakened synaptic connectivity, a hallmark observed in multiple ASD models. These synaptic impairments elucidate the structural basis for disrupted neural circuits that underlie the observed behavioral deficits.
Molecular assays further delineated the mechanism, highlighting a cascade wherein maternal SCH perturbs canonical Wnt signaling, leading to diminished transcriptional activation of BDNF. This downregulated BDNF expression compromises neuronal survival and plasticity during critical developmental windows, ultimately translating to long-lasting neurobehavioral consequences. The study’s data suggest a direct link between thyroid hormone insufficiency, Wnt pathway dysregulation, and subsequent neurotrophic deficits.
Intriguingly, the investigators also explored downstream mediators, noting alterations in glycogen synthase kinase 3 beta (GSK-3β) activity—a key kinase negatively regulating Wnt signaling. Elevated GSK-3β phosphorylation status in SCH offspring brains implicates its involvement as a modulatory node influencing both Wnt and BDNF pathways. Targeting GSK-3β pharmacologically could therefore represent a viable therapeutic strategy to restore signaling balance and mitigate neurodevelopmental impairment.
The translational implications of these findings are profound. Subclinical hypothyroidism, often overlooked in prenatal care, may silently predispose offspring to neurodevelopmental challenges that manifest as ASD phenotypes. Early identification and intervention targeting the Wnt/BDNF axis might offer new avenues to prevent or ameliorate such outcomes. The study advocates for heightened vigilance in maternal thyroid screening and suggests that adjunct therapies modulating Wnt and neurotrophic signaling hold therapeutic promise.
Moreover, the work advances a mechanistic framework that integrates endocrine disruptions with neural circuit malformations characteristic of autism, moving beyond correlative studies to molecular causality. This rigorous mechanistic elucidation paves the way for biomarker development and targeted treatments that could significantly improve quality of life for affected individuals.
The authors also stress the need for further research to validate these findings in human populations and to explore the therapeutic potential of modulating Wnt/BDNF signaling in clinical contexts. They propose future studies employing genetic and pharmacological tools to precisely manipulate these pathways during critical prenatal and early postnatal periods, aiming to reverse or mitigate autism-like phenotypes.
Additionally, this research highlights the broader significance of maternal health on offspring neurodevelopment, underscoring that even mild maternal endocrine anomalies can have lasting neurobiological consequences. This insight stresses the importance of comprehensive prenatal monitoring and suggests revisiting current guidelines surrounding thyroid function assessments in pregnancy.
Beyond the immediate scope of autism, the elucidated Wnt/BDNF dysregulation may also intersect with other neuropsychiatric conditions linked to maternal thyroid dysfunction, including anxiety disorders and cognitive impairments. Thus, the study opens a wider dialogue on maternal-fetal health interactions and their impacts on long-term neurological outcomes.
The utilization of sophisticated molecular techniques, behavioral paradigms, and ultrastructural analyses in this study represents a benchmark for neurodevelopmental research, demonstrating how multidisciplinary approaches can unravel complex pathophysiologies. The integration of in vivo rodent models with molecular assays delivers a compelling narrative from gene regulation to behavior—a crucial framework for modern neuroscience.
In summary, this pioneering research unearths a critical role for the Wnt/BDNF pathway in mediating maternal SCH-induced autism-like phenotypes in offspring rats. By unraveling the molecular and behavioral sequelae of thyroid hormone insufficiency, it offers novel insights into the developmental origins of ASD and highlights promising molecular targets for intervention.
As autism’s global prevalence continues to rise, insights such as these emphasize the imperative for early diagnosis, prevention, and tailored therapies grounded in a deep understanding of neurobiology. This study thus heralds a new chapter in unraveling the intricate dance between endocrine health and brain development, bringing the scientific community closer to unmasking autism’s enigmatic origins and ultimately improving clinical outcomes.
Subject of Research: Maternal subclinical hypothyroidism-induced autism-like phenotypes in offspring rats and the role of the Wnt/BDNF signaling pathway.
Article Title: The role of the Wnt/BDNF pathway in maternal SCH-induced autism-like phenotypes in offspring rats: behavioral and molecular mechanisms.
Article References:
Liu, D., Tao, K., Sun, Y. et al. The role of the Wnt/BDNF pathway in maternal SCH-induced autism-like phenotypes in offspring rats: behavioral and molecular mechanisms. Transl Psychiatry 15, 387 (2025). https://doi.org/10.1038/s41398-025-03570-6
Image Credits: AI Generated
