| First Author | Zhang F | Year | 2021 |
| Journal | Transl Psychiatry | Volume | 11 |
| Issue | 1 | Pages | 99 |
| PubMed ID | 33542189 | Mgi Jnum | J:331672 |
| Mgi Id | MGI:6804597 | Doi | 10.1038/s41398-021-01233-w |
| Citation | Zhang F, et al. (2021) Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice. Transl Psychiatry 11(1):99 |
| abstractText | 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. |
