Wnt/BDNF pathway mediates autism-like behaviors induced by prenatal subclinical hypothyroidism in male neonatal rats

Abstract

Epidemiological studies have illuminated that abnormal maternal thyroid function in early pregnancy escalates the risk of autism spectrum disorder (ASD) in offspring by nearly fourfold. However, the exact mechanism by which maternal thyroid dysfunction affects the risk of ASD in the offspring remains unknown. Early pregnancy emerges as a pivotal juncture for fetal brain development, with the fetus heavily reliant on maternal thyroid hormones for its neurological maturation. Our investigation unveils a striking correlation: mothers afflicted by perinatal subclinical hypothyroidism (SCH) tend to have male offspring displaying marked ASD-like behavioral anomalies, typified by conspicuous diminution in social interactions and repetitive behavioral patterns. Furthermore, we discerned a substantial reduction in neuron count within critical brain regions among offspring of SCH mothers, suggestive of underlying neurodegeneration or developmental impediments. Moreover, diminished levels of brain-derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), and Bcl-2 were noted in the hippocampal region of SCH offspring, juxtaposed with a noteworthy upregulation of mTOR expression and downregulation of Wnt. These findings coalesce to suggest that the Wnt-mediated signaling pathway, in concert with its interplay with the downstream target BDNF, might underpin one of the mechanisms by which maternal SCH predisposes offspring to autism-like behaviors.