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Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models

Molecular Psychiatry volume 27, pages 3355–3366 (2022)Cite this article

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Abstract

Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that histone lysine 4 dimethylation (H3K4me2), a histone mark linked to gene activation, is significantly decreased in the prefrontal cortex (PFC) of autistic human patients and mutant mice with the deficiency of top-ranking autism risk factor Shank3 or Cul3. A brief treatment of the autism models with highly potent and selective inhibitors of the H3K4me2 demethylase LSD1 (KDM1A) leads to the robust rescue of core symptoms of autism, including social deficits and repetitive behaviors. Concomitantly, LSD1 inhibition restores NMDA receptor function in PFC and AMPA receptor-mediated currents in striatum of Shank3-deficient mice. Genome-wide RNAseq and ChIPseq reveal that treatment of Shank3-deficient mice with the LSD1 inhibitor restores the expression and H3K4me2 occupancy of downregulated genes enriched in synaptic signaling and developmental processes. The immediate early gene tightly linked to neuronal plasticity, Egr1, is on the top list of rescued genes. The diminished transcription of Egr1 is recapitulated in PFC of autistic human patients. Overexpression of Egr1 in PFC of Shank3-deficient mice ameliorates social preference deficits. These results have for the first time revealed an important role of H3K4me2 abnormality in ASD pathophysiology, and the therapeutic potential of targeting H3K4me2 demethylase LSD1 or the downstream molecule Egr1 for ASD.

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Fig. 1: Autistic patients and Shank3-deficient mice have diminished H3K4 dimethylation in PFC neurons, which is reversed by histone demethylase 1 (LSD1) inhibition.
Fig. 2: Treatment with LSD1 inhibitors rescues autism-like social deficits and repetitive behaviors in Shank3-deficient mice.
Fig. 3: Treatment with LSD1 inhibitor rescues social deficits in Cul3 model of autism.
Fig. 4: Treatment of Shank3-deficient mice with LSD1 inhibitor rescues NMDAR hypofunction in PFC and restores synaptic response in striatum.
Fig. 5: Treatment with LSD1 inhibitor induces genome-wide restoration of down-regulated genes in PFC of Shank3-deficient mice.
Fig. 6: Overexpression of Egr1 in PFC of Shank3-deficient mice rescues autism-like social deficits.
Fig. 7: Treatment with LSD1 inhibitor induces genome-wide restoration of H3K4me2 occupancy at gene promoters in PFC of Shank3-deficient mice.

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Data availability

The RNAseq and ChIPseq data generated in this study have been deposited in the GEO public repository under accession code GSE193380.

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Acknowledgements

We thank Dr. Craig Powell at University of Alabama at Birmingham for kindly providing breeding pairs of Shank3E13 mice. We thank Dr. Mohamed Kabbaj at Florida State University for kindly providing Egr1 AAV and GFP AAV. We also thank Xiaoqing Chen for excellent technical support and Luciana R. Frick for taking some confocal images. This work was supported by: Nancy Lurie Marks Family Foundation (ZY), National Institutes of Health (MH112237, MH126443) (ZY), National Center for Advancing Translational Sciences of the National Institutes of Health (KL2TR001413) (MR), and National Institutes of Health (MH104341, MH117790) (SA).

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA

    Maximiliano Rapanelli, Jamal B. Williams, Kaijie Ma, Fengwei Yang, Ping Zhong, Rajvi Patel, Manasa Kumar, Luye Qin, Benjamin Rein, Zi-Jun Wang & Zhen Yan

  2. Department of Psychiatry; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Bibi Kassim, Behnam Javidfar, Lizette Couto & Schahram Akbarian

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  1. Maximiliano Rapanelli
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Contributions

MR performed some behavioral, immunocytochemical, biochemical experiments, bioinformatic analyses, and wrote the draft. JW and FY performed bioinformatic analyses. KM performed behavioral experiments. PZ carried out electrophysiological experiments. RP and MK performed some behavioral and biochemical assays. LQ, BR, Z-JW carried out qPCR or immunocytochemical experiments. BK, BJ, and LC extracted neuronal nuclei for ChIPseq experiments. SA oversaw ChIPseq studies. ZY designed experiments, supervised the project and wrote the paper. None of the authors have the financial interest related to this work.

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Correspondence to Zhen Yan.

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Rapanelli, M., Williams, J.B., Ma, K. et al. Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models. Mol Psychiatry 27, 3355–3366 (2022). https://doi.org/10.1038/s41380-022-01508-8

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