Maternal Immune Activation Disrupts Epigenomic and Functional Maturation of Cortical Excitatory Neurons

Lai, C.-Y.; Arzavala, J.; Duarte, A. P.; Wang, S.; Li, J.; Liu, H.; Osteen, J.; Castanon, R. G.; Nery, J. R.; Powell, S. B.; Ecker, J. R.; Mukamel, E. A.; Behrens, M. M.

doi:10.1101/2025.04.28.651094

bioRxiv · 10.1101/2025.04.28.651094

Maternal Immune Activation Disrupts Epigenomic and Functional Maturation of Cortical Excitatory Neurons

Lai, C.-Y.·Arzavala, J.·Duarte, A. P.·Wang, S.·Li, J.·Liu, H.·Osteen, J.·Castanon, R. G.·Nery, J. R.·Powell, S. B.·Ecker, J. R.·Mukamel, E. A.·Behrens, M. M.

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Abstract

Elevated levels of maternal pro-inflammatory cytokines during gestation can disrupt offspring neural development, increasing the risk of neurodevelopmental disorders. We studied the effects of Poly(I:C)-induced maternal immune activation (PIC-MIA) during mid-gestation on developing cortical excitatory neurons DNA methylation and transcriptome. PIC-MIA disrupted the developmental regulation of synapse-related genes and of genes implicated in autism spectrum disorders. Genomic regions that gain or lose DNA methylation during normal development were altered following PIC-MIA, including neurodevelopmental transcription factor binding sites. The DNA methylation and transcriptional changes were consistent with a delay in excitatory neuron maturation. Whole-cell recordings showed that PIC-MIA preferentially altered the physiological development of layer 5 excitatory neurons. Taken together, present results suggest that alterations in the epigenome, through the disruption of circuit formation, may drive the long-term consequences of maternal infection during gestation.

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Lai, C.-Y., Arzavala, J., Duarte, A. P., Wang, S., Li, J., Liu, H., Osteen, J., Castanon, R. G., Nery, J. R., Powell, S. B., Ecker, J. R., Mukamel, E. A., Behrens, M. M.. 2025-04-29. Maternal Immune Activation Disrupts Epigenomic and Functional Maturation of Cortical Excitatory Neurons. https://doi.org/10.1101/2025.04.28.651094

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