{"doi":"10.1038/s41398-021-01233-w","title":"Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice","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.","journal":"Translational Psychiatry","year":2021,"id":168366,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":254844,"name":"Benjamin Rein","orcid":"0000-0002-9202-4469","position":1,"is_corresponding":false},{"id":485322,"name":"Ping Zhong","orcid":"0000-0002-8891-344X","position":2,"is_corresponding":false},{"id":697667,"name":"Treefa Shwani","orcid":null,"position":3,"is_corresponding":false},{"id":634344,"name":"Megan Conrow‐Graham","orcid":"0000-0002-9996-0786","position":4,"is_corresponding":false},{"id":104706,"name":"Zijun Wang","orcid":"0000-0002-2095-2151","position":5,"is_corresponding":false},{"id":53359,"name":"Zhen Yan","orcid":"0000-0002-3519-9596","position":6,"is_corresponding":false},{"id":317263,"name":"Freddy Zhang","orcid":"0000-0001-6769-8130","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:46:02.603031Z","pmid":"33542189","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}