Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice

• DOI: 10.1038/s41398-021-01233-w
• Publication Date: 2021-02-04T14:26:16Z
• Authors: Freddy Zhang; Benjamin Rein; Ping Zhong; Treefa Shwani; Megan Conrow-Graham; Zi-Jun Wang; Zhen Yan
• Keywords: Male; 0301 basic medicine; Autism Spectrum Disorder; Microfilament Proteins; Neurosciences. Biological psychiatry. Neuropsychiatry; Nerve Tissue Proteins; Article; 3. Good health; Histones; Disease Models, Animal; Mice; 03 medical and health sciences; Animals; RC321-571

Autism spectrum disorder (ASD) is a lifelong developmental characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications chromatin remodeling, have been implicated in ASD pathology, provides promising therapeutic target for ASD. Haploinsufficiency the SHANK3 gene causally linked to ASD, so adult (3-5 months old) Shank3-deficient male mice were used this drug discovery study. We found that combined administration class I deacetylase inhibitor Romidepsin demethylase LSD1 GSK-LSD1 persistently ameliorated autism-like preference deficits, while each individual alone was largely ineffective. Another abnormality mice, heightened aggression, also alleviated dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels NMDA receptor subunits prefrontal cortex (PFC) resulting elevated synaptic expression receptors restoration NMDAR function PFC pyramidal neurons. These results offered novel pharmacological intervention strategy beyond early periods.