Developmental Dysregulation of Synaptic and Myelin-Related Genes in Frontal Cortex and Serum Infrared Spectroscopy Signature in the Valproic Acid Model of Autism

Sousa, C. A.; Kroll, J.; Brandao, J. A.; Ruschi, S.; Morais, C. L.; dos Santos, M. C. D.; Bessa, R. d. S.; Lima, K. M.; de Souza, S. J.; Romcy-Pereira, R. N.

doi:10.1101/2025.10.04.680465

bioRxiv · 10.1101/2025.10.04.680465

Developmental Dysregulation of Synaptic and Myelin-Related Genes in Frontal Cortex and Serum Infrared Spectroscopy Signature in the Valproic Acid Model of Autism

Sousa, C. A.·Kroll, J.·Brandao, J. A.·Ruschi, S.·Morais, C. L.·dos Santos, M. C. D.·Bessa, R. d. S.·Lima, K. M.·de Souza, S. J.·Romcy-Pereira, R. N.

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Abstract

Neural circuits emerge during development through dynamic interactions between genetic instructions and environmental cues that shape cell fate, connectivity, and the timing of myelination. In developmental disorders such as autism, abnormalities in sensory processing, social cognition, and motor behavior are thought to arise from disruptions in these processes. Here, we investigated early-life molecular changes following prenatal exposure to valproic acid (VPA), an environmentally induced model of autism. We integrated cortical gene expression analysis using RNA sequencing/qPCR, alternative splicing profiling, in situ myelin quantification, plasma serotonin determination, and machine learning-assisted classification of blood serum molecular profiles using infrared spectroscopic (FTIR) data. Our findings revealed downregulation of myelin-associated genes and upregulation of synapse-related genes in the frontal cortex of young VPA-exposed rats. qPCR confirmed reduced cortical expression of Mobp and PLP1 along with increased Penk and C1ql3 expression. Alternative splicing analysis identified numerous novel transcript variants, enriched in synaptic-related genes, indicating widespread post-transcriptional remodeling in VPA animals. These molecular alterations were accompanied by a significant reduction in myelin content within the cingulate and motor cortex of adult animals. Peripheral molecular profiling showed elevated plasma serotonin in VPA-treated animals and demonstrated that a support vector machine trained on serum FTIR spectra classified VPA-exposed animals with 85% accuracy. Collectively, our findings suggest that prenatal VPA exposure induces early dysregulation of myelin organization, synaptic gene networks, and RNA splicing programs, potentially leading to long-term impairments in neuronal communication and processing efficiency. Furthermore, our results highlight serum spectroscopic signatures as promising peripheral biomarkers for autism, warranting further investigation.

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Sousa, C. A., Kroll, J., Brandao, J. A., Ruschi, S., Morais, C. L., dos Santos, M. C. D., Bessa, R. d. S., Lima, K. M., de Souza, S. J., Romcy-Pereira, R. N.. 2025-10-05. Developmental Dysregulation of Synaptic and Myelin-Related Genes in Frontal Cortex and Serum Infrared Spectroscopy Signature in the Valproic Acid Model of Autism. https://doi.org/10.1101/2025.10.04.680465

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