Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice.
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| Abstract |
Autism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of the SHANK3 gene is causally linked to ASD, so adult (3-5 months old) Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adult Shank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adult Shank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.
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| Authors | Freddy Zhang, Benjamin Rein, Ping Zhong, Treefa Shwani, Megan Conrow-Graham, Zi-Jun Wang, Zhen Yan |
| Journal | Translational psychiatry (Transl Psychiatry) Vol. 11 Issue 1 Pg. 99 (02 04 2021) ISSN: 2158-3188 [Electronic] United States |
| PMID | 33542189 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
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