AUTHOR=Su Yueqing , Lian Jiamei , Chen Shiyan , Zhang Wenchang , Deng Chao 

TITLE=Epigenetic histone acetylation modulating prenatal Poly I:C induced neuroinflammation in the prefrontal cortex of rats: a study in a maternal immune activation model

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=16

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2022.1037105

DOI=10.3389/fncel.2022.1037105

ISSN=1662-5102

ABSTRACT=<p><bold>Introduction:</bold> Neuroinflammation in the central nervous system, particularly the prefrontal cortex (PFC), plays a role in the pathogenesis of schizophrenia, which has been found to be associated with maternal immune activation (MIA). Recent evidence suggests that epigenetic regulation involves in the MIA-induced neurodevelopmental disturbance. However, it is not well-understood how epigenetic modulation is involved in the neuroinflammation and pathogenesis of schizophrenia.</p><p><bold>Methods:</bold> This study explored the modulation of histone acetylation in both neuroinflammation and neurotransmission using an MIA rat model induced by prenatal polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure, specifically examining those genes that were previously observed to be impacted by the exposure, including a subunit of nuclear factor kappa-B (<italic>Rela</italic>), Nod-Like-Receptor family Pyrin domain containing 3 (<italic>Nlrp3</italic>), NMDA receptor subunit 2A (<italic>Grin2a</italic>), 5-HT2A (<italic>Htr2a</italic>), and GABAA subunit β3 (<italic>Gabrb3</italic>).</p><p><bold>Results:</bold> Our results revealed global changes of histone acetylation on H3 (H3ace) and H4 (H4ace) in the PFC of offspring rats with prenatal Poly I:C exposure. In addition, it revealed enhancement of both H3ace and H4ace binding on the promoter region of <italic>Rela</italic>, as well as positive correlations between <italic>Rela</italic> and genes encoding histone acetyltransferases (HATs) including CREB-binding protein (CBP) and E1A-associated protein p300 (EP300). Although there was no change in H3ace or H4ace enrichment on the promoter region of <italic>Nlrp3</italic>, a significant enhancement of histone deacetylase 6 (HDAC6) binding on the promoter region of <italic>Nlrp3</italic> and a positive correlation between <italic>Nlrp3</italic> and <italic>Hdac6</italic> were also observed. However, prenatal Poly I:C treatment did not lead to any specific changes of H3ace and H4ace on the promoter region of the target genes encoding neurotransmitter receptors in this study.</p><p><bold>Discussion:</bold> These findings demonstrated that epigenetic modulation contributes to NF-κB/NLRP3 mediated neuroinflammation induced by prenatal Poly I:C exposure <italic>via</italic> enhancement of histone acetylation of H3ace and H4ace on <italic>Rela</italic> and HDAC6-mediated NLRP3 transcriptional activation. This may further lead to deficits in neurotransmissions and schizophrenia-like behaviors observed in offspring.</p>