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Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice.
- Source :
-
Molecular psychiatry [Mol Psychiatry] 2020 Oct; Vol. 25 (10), pp. 2517-2533. Date of Electronic Publication: 2019 Jan 18. - Publication Year :
- 2020
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Abstract
- Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activity-regulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.
- Subjects :
- Animals
Autistic Disorder genetics
Disease Models, Animal
Female
Haploinsufficiency
Histone-Lysine N-Methyltransferase metabolism
Histones metabolism
Male
Methylation drug effects
Mice
Microfilament Proteins genetics
Nerve Tissue Proteins genetics
Prefrontal Cortex drug effects
Prefrontal Cortex metabolism
Quinazolines pharmacology
Autistic Disorder drug therapy
Histone-Lysine N-Methyltransferase antagonists & inhibitors
Microfilament Proteins deficiency
Nerve Tissue Proteins deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5578
- Volume :
- 25
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 30659288
- Full Text :
- https://doi.org/10.1038/s41380-019-0351-2