{"doi":"10.1016/j.bpsgos.2024.100289","title":"MEF2C Hypofunction in GABAergic Cells Alters Sociability and Prefrontal Cortex Inhibitory Synaptic Transmission in a Sex-Dependent Manner","abstract":"Heterozygous mutations or deletions of MEF2C cause a neurodevelopmental disorder termed MEF2C Haploinsufficiency Syndrome (MCHS), characterized by autism spectrum disorder (ASD) and neurological symptoms. In mice, global Mef2c heterozygosity produced multiple MCHS-like phenotypes. MEF2C is highly expressed in multiple cell types of the developing brain, including GABAergic inhibitory neurons, but the influence of MEF2C hypofunction in GABAergic neurons on MCHS-like phenotypes remains unclear. We employed GABAergic cell type-specific manipulations to study mouse Mef2c heterozygosity in a battery of MCHS-like behaviors. We also performed electroencephalography, single-cell transcriptomics, and patch-clamp electrophysiology and optogenetics to assess the impact of Mef2c haploinsufficiency on gene expression and prefrontal cortex microcircuits. Mef2c heterozygosity in developing GABAergic cells produced female-specific deficits in social preference and altered approach-avoidance behavior. In female, but not male, mice, we observed that Mef2c heterozygosity in developing GABAergic cells produced: 1) differentially expressed genes in multiple cell types, including parvalbumin (PV)-expressing GABAergic neurons, 2) baseline and social-related frontocortical network activity alterations, and 3) reductions in PV cell intrinsic excitability and inhibitory synaptic transmission onto deep-layer pyramidal neurons. MEFC hypofunction in female, but not male, developing GABAergic cells is important for typical sociability and approach-avoidance behaviors and normal PV inhibitory neuron function in the prefrontal cortex of mice. While there is no apparent sex bias in ASD symptoms of MCHS, our findings here suggest that GABAergic cell-specific dysfunction in females with MCHS might contribute disproportionately to sociability symptoms.","journal":"Biological Psychiatry Global Open Science","year":2024,"id":441769,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":717179,"name":"Jeffrey A. Rumschlag","orcid":"0000-0003-4593-5590","position":1,"is_corresponding":false},{"id":311331,"name":"Tsvetkov Ea","orcid":"0000-0002-6784-0907","position":2,"is_corresponding":false},{"id":1255311,"name":"Divya S. Proper","orcid":null,"position":3,"is_corresponding":false},{"id":373687,"name":"Hainan Lang","orcid":"0000-0003-2210-7856","position":4,"is_corresponding":false},{"id":311328,"name":"Stefano Berto","orcid":"0000-0001-9028-9458","position":5,"is_corresponding":false},{"id":287639,"name":"Ahlem Assali","orcid":"0000-0002-5863-3682","position":6,"is_corresponding":false},{"id":287641,"name":"Christopher W. Cowan","orcid":"0000-0001-5472-3296","position":7,"is_corresponding":false},{"id":249609,"name":"Jennifer Y. Cho","orcid":"0000-0002-2138-7510","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:01:11.152920Z","pmid":"38390348","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":[]}