Chronic HDACi emends microglial differentiation and neurological disease in a mouse model of intellectual disability

Alam, M. S.; Padmanabhan, P. K.; McArdle, R.; Lopez-Ramirez, A.; MysoreRajashekara, A.; Knopp, J.; Kim, G.; Centeo, M. V.; Apkarian, A. V.; Swarup, V.; Haldar, K.

doi:10.1101/2025.05.01.651719

bioRxiv · 10.1101/2025.05.01.651719

Chronic HDACi emends microglial differentiation and neurological disease in a mouse model of intellectual disability

Alam, M. S.·Padmanabhan, P. K.·McArdle, R.·Lopez-Ramirez, A.·MysoreRajashekara, A.·Knopp, J.·Kim, G.·Centeo, M. V.·Apkarian, A. V.·Swarup, V.·Haldar, K.

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Abstract

Defect in lysine-specific methyltransferase 2D (KMT2D) underlies a rare intellectual disability disorder, Kabuki Syndrome (KS). We show that in addition to reduction in post-natal neurogenesis, KS mice present small, arrested hippocampal microglia which single cell RNA sequence analyses revealed as globally downregulated, occupying neither activated nor surveillance states. Weekly administration of a triple combination formulation (TCF) containing the FDA-approved HDAC inhibitor Vorinostat, HPBCD and PEG-400 for three months, boosted microglia. Transcriptomic, pseudotime cell trajectory analyses, imaging and behavioral data suggest that TCF differentiated KS microglia from arrested to non-diseased and non-activated surveillance forms by selective acetylation of histone H3, that restored the open chromatin mark H3K4me3 independent of Kmt2D, to improve cognitive and nociceptive responses. Wild-type microglia showed no substantial transcriptional or histone changes, intimating normal heterochromatin resisted TCF. These findings reveal a novel chromatin-mediated mechanism of microglial differentiation uncoupled from activation, with therapeutic potential for KS and related disorders.

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Alam, M. S., Padmanabhan, P. K., McArdle, R., Lopez-Ramirez, A., MysoreRajashekara, A., Knopp, J., Kim, G., Centeo, M. V., Apkarian, A. V., Swarup, V., Haldar, K.. 2025-05-07. Chronic HDACi emends microglial differentiation and neurological disease in a mouse model of intellectual disability. https://doi.org/10.1101/2025.05.01.651719

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