Prenatal valproic acid exposure alters striatal proteomic signatures associated with autism spectrum disorder in mice
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Published on: October 17, 2025
Eun Hwa Jo1,2, Yunjung Choi2, Han-Byeol Kim3
1Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Insights
Prenatal exposure to valproic acid (VPA) alters striatal proteins, impacting synaptic function and contributing to autism spectrum disorder (ASD)-like behaviors in mice. This study reveals key molecular changes in the brain following VPA exposure.
Area of Science:
- Neuroscience
- Proteomics
- Developmental Biology
Background:
- Prenatal exposure to valproic acid (VPA) is a known risk factor for autism spectrum disorder (ASD).
- Molecular mechanisms underlying VPA's effects on brain development and ASD phenotypes are not fully understood.
- Previous studies reported behavioral and anatomical changes in VPA-exposed animal models.
Purpose of the Study:
- To investigate the subregion-specific proteomic changes in the mouse striatum following prenatal valproic acid (VPA) exposure.
- To identify molecular pathways and key proteins affected by VPA exposure that may contribute to autism spectrum disorder (ASD)-like phenotypes.
- To provide histological validation for proteomic findings related to specific proteins.
Main Methods:
- Quantitative proteomics using tandem mass tag (TMT) labeling to profile protein expression in the striatum of VPA-exposed mice.
- Behavioral assessments to confirm ASD-like phenotypes (e.g., reduced weight, self-grooming).
- Functional enrichment analysis, protein-protein interaction network analysis, and quantitative immunofluorescence for validation.
Main Results:
- VPA exposure led to reduced body and brain weights and increased repetitive self-grooming behavior in mice.
- Proteomic analysis identified 101 differentially expressed proteins (DEPs), with significant alterations in pathways related to synaptic transmission, neuronal development, and oxidative stress.
- Downregulation of key proteins like parvalbumin (PVALB) and metallothioneins (MT1, MT2, MT3) was observed, suggesting impaired inhibitory signaling and redox regulation.
- Histological analysis confirmed reduced PVALB immunoreactivity in the striatum.
Conclusions:
- Prenatal VPA exposure significantly alters striatal proteome, affecting synaptic function, neuronal development, and redox balance.
- Key proteins such as PVALB and metallothioneins are implicated in VPA-induced neurobiological changes and ASD-like behaviors.
- These findings offer subregion-specific molecular insights into the pathogenesis of ASD following prenatal VPA exposure.
Abstract:
Prenatal exposure to valproic acid (VPA), a widely prescribed antiepileptic and mood‑stabilizing drug, is a well-established environmental risk factor for autism spectrum disorder (ASD). Although behavioral and anatomical abnormalities have been reported in VPA-exposed animal models, the underlying molecular mechanisms within specific brain regions remain unclear. In this study, we used tandem mass tag (TMT)-based quantitative proteomics to profile protein expression in the striatum of 9-10-week-old mice prenatally exposed to VPA. Behavioral assessment confirmed core ASD-like phenotypes, including reduced body and brain weights and increased repetitive self-grooming behavior. Proteomic profiling identified 101 differentially expressed proteins (DEPs), with 47 upregulated and 54 downregulated in VPA-exposed mice. Functional enrichment analysis revealed significant involvement of pathways related to synaptic transmission, neuronal development, metal ion homeostasis, oxidative stress response, and excitation/inhibition (E/I) balance. Notably, proteins such as parvalbumin (PVALB), NR2F1, and metallothioneins (MT1, MT2, MT3) were markedly downregulated, implicating impaired inhibitory signaling and redox regulation. Importantly, quantitative PVALB immunofluorescence analysis provided histological validation of the proteomic findings, revealing a significant reduction of PVALB immunoreactivity in the dorsolateral striatum, with a non-significant trend toward reduction in the dorsomedial striatum. Additionally, protein-protein interaction network analysis identified PVALB and MT2 as central hub proteins linking synaptic, glial, and oxidative stress-related modules, highlighting disrupted striatal network organization. Collectively, these findings provide subregion-specific molecular and histological insight into how prenatal VPA exposure alters striatal neurobiology and contributes to ASD-like behavioral phenotypes. Proteomic data are available via ProteomeXchange (PXD067574).