Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder, with lead (Pb) exposure increasingly linked to its risk. However, the molecular mechanisms linking Pb to ASD remain poorly understood. This study established a postnatal Pb-exposed mouse model and employed the three-chamber social test and the marble-burying test to assess ASD-like behavioral phenotypes. The Pb levels in both blood and the hippocampus were quantified, and hippocampal neurons were assessed for morphological alterations. Moreover, a Tandem Mass Tag (TMT)-based quantitative proteomics approach was applied to elucidate the underlying mechanisms. Neurobehavioral experiments revealed Pb-exposed C57BL/6 offspring exhibited reduced social interaction and novelty preference along with increased repetitive marble-burying behavior. The Pb levels in both the blood and hippocampus of Pb-treated mice were significantly elevated compared with those of control animals. Postnatal Pb exposure resulted in a reduction in the neuronal numbers and disorganized neuronal arrangement in the hippocampus. A total of 66 proteins were identified as being differentially expressed after postnatal Pb exposure. Among them, 34 differentially expressed proteins were common in both Pb exposure groups, with 33 downregulated and 1 upregulated. Bioinformatic analysis revealed multi-pathway regulation involved in Pb-induced neurodevelopmental disorders, including dysregulation of synaptic signaling, abnormal activation of neuron apoptosis, and neuroinflammation. Notably, the SYT10/IGF-1 signaling pathway may play a potential key role. These findings enhance understanding of Pb-induced autism-like behaviors, providing novel proteomic insights into the etiology of ASD.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social communication and repetitive behaviors, involving various brain regions. Emerging evidence highlights the critical role of the cerebellum in the pathophysiology of autism; however, the underlying molecular mechanisms remain poorly understood. This study aimed to establish a prenatal valproic acid (VPA)-induced mouse model of ASD and explore the potential molecular mechanisms underlying cerebellar ASD-like phenotypes through DIA-based proteomics and bioinformatics analyses. Significant cognitive impairment and anxiety-like behaviors were detected using an open field test and novel object test following VPA exposure, respectively. Additionally, reduced numbers of Purkinje cells with irregular arrangement were observed in the cerebellum. Furthermore, cerebellar proteomics analyses revealed that they identified 193 differentially expressed proteins (DEPs) involved in multiple pathways, including axon guidance, glutamatergic synapse, long-term potentiation, and calcium signaling, among others. Notably, dysfunction of glutamate receptor signaling and disruptions in axon-guidance signaling appear to be major molecular mechanisms underlying cerebellar impairment. Together, these findings suggest that Grin2b may serve as a critical molecule linking synaptic neurotransmission and neurodevelopmental disorders. Thus, Grin2b may represent a potential therapeutic target for addressing cognitive impairment in ASD.