{"doi":"10.1101/2024.01.27.575409","title":"Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction","abstract":"SUMMARY Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity, and their dysfunction is consistently observed in myriad brain diseases. To understand how immune complement dysregulation – a prevalent locus of brain disease etiology – in PV cells may drive disease pathogenesis, we have developed a transgenic mouse line that permits cell-type specific overexpression of the schizophrenia-associated complement component 4 ( C4 ) gene. We found that overexpression of mouse C4 ( mC4 ) in PV cells causes sex-specific behavioral alterations and concomitant deficits in synaptic connectivity and excitability of PV cells of the prefrontal cortex. Using a computational network, we demonstrated that these microcircuit deficits led to hyperactivity and disrupted neural communication. Finally, pan-neuronal overexpression of mC4 failed to evoke the same deficits in behavior as PV-specific mC4 overexpression, suggesting that C4 perturbations in fast-spiking neurons are more harmful to brain function than pan-neuronal alterations. Together, these results provide a causative link between C4 and the vulnerability of PV cells in brain disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":493693,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"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":1110871,"name":"Rhushikesh A. Phadke","orcid":"0009-0008-7097-7593","position":1,"is_corresponding":false},{"id":542893,"name":"María Salgado","orcid":"0000-0003-1551-7216","position":2,"is_corresponding":false},{"id":7643,"name":"Alison Brack","orcid":"0000-0002-4401-6501","position":3,"is_corresponding":false},{"id":565687,"name":"Jian Carlo Nocon","orcid":"0000-0001-9879-1549","position":4,"is_corresponding":false},{"id":1257772,"name":"Sonia Bolshakova","orcid":null,"position":5,"is_corresponding":false},{"id":1257773,"name":"Jaylyn R. Grant","orcid":null,"position":6,"is_corresponding":false},{"id":1257774,"name":"Nicole M. Padró Luna","orcid":null,"position":7,"is_corresponding":false},{"id":565688,"name":"Kamal Sen","orcid":"0000-0002-9741-0836","position":8,"is_corresponding":false},{"id":753931,"name":"Alberto Cruz‐Martín","orcid":"0000-0002-3271-7220","position":9,"is_corresponding":false},{"id":1163369,"name":"Luke A. Fournier","orcid":"0009-0003-9352-8225","position":0,"is_corresponding":true}],"reference_count":168,"raw_metadata":null,"created_at":"2026-07-19T02:09:03.883685Z","pmid":"38328248","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":[]}