{"doi":"10.1101/2025.05.20.655207","title":"Inhibitory Circuit Compensations in Female and Male Mice: Increased Synaptic Output Offsets Reduced Parvalbumin Interneuron Density","abstract":"Summary Parvalbumin inhibitory interneurons (PV-INs) are critical regulators of excitatory/inhibitory balance in the cortex, and their dysfunction has been observed in various neurological disorders. Despite increasing recognition of sex differences in brain function, little is known about how PV-INs differ between males and females under healthy conditions. Previous work has pointed to sex differences in PV-IN vulnerability in disease and injury models. Here, we investigated sex differences in PV-IN characteristics, connectivity, and function in the retrosplenial cortex (RSC) of healthy mice. We found that female mice have significantly fewer PV-INs in the RSC compared to males, yet exhibit comparable memory induced neuronal activation (fos expression). Despite their lower numbers, female PV-INs displayed greater synaptic connectivity, as evidenced by increased synaptotagmin-2 (Syt-2) puncta per PV-IN and higher axonal bouton density. Additionally, fewer female PV-INs were surrounded by perineuronal nets (PNNs), suggesting greater plasticity in female inhibitory networks. From ex vivo slice electrophysiology recordings we observed greater excitability in female PV-INs compared to male PV-INs and, a reduced incidence of IPSCs. These findings indicate that female mice may compensate for reduced PV-IN numbers through enhanced synaptic output, preserving inhibitory function in the RSC. Finally, using spatial transcriptomic profiling of PV-INs we observed a number of differentially expressed genes that are consistent with the observed structural and functional differences between female and male PV-INs. Understanding these sex-specific inhibitory mechanisms is crucial for developing more targeted interventions for conditions involving PV-IN impairment and for understanding sex specific vulnerabilities to certain conditions such as Alzheimer’s disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566502,"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":0.9471,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1167470,"name":"Dylan J. Terstege","orcid":"0000-0002-5903-0875","position":1,"is_corresponding":false},{"id":1470568,"name":"Shi Chen Xu","orcid":null,"position":2,"is_corresponding":false},{"id":1167984,"name":"Bo Young Ahn","orcid":null,"position":3,"is_corresponding":false},{"id":1275707,"name":"Heewon Seo","orcid":"0000-0001-6218-8609","position":4,"is_corresponding":false},{"id":35751,"name":"Derya Sargin","orcid":"0000-0001-8018-4329","position":5,"is_corresponding":false},{"id":1167472,"name":"Jonathan R. Epp","orcid":"0000-0002-7968-8973","position":6,"is_corresponding":false},{"id":1470567,"name":"Nadia Khoshbaf Khiabanian","orcid":null,"position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:36.440192Z","pmid":null,"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":[]}