{"doi":"10.1007/s12031-024-02260-0","title":"Regulation of Hippocamposeptal Synaptic Transmission by GABABRs Is Altered in 5XFAD Mice in a Sex- and Age-Dependent Manner","abstract":"Abstract Hippocamposeptal (HS) neurons send GABAergic projections from the hippocampus to the medial septum/diagonal band of Broca (MS/DBB) as part of a reciprocal loop that is critical for memory. HS neurons are proposed to be particularly sensitive to the deleterious effects of pathological exposure to amyloid-β (Aβ), as would occur during Alzheimer’s disease (AD). However, it is not known how HS GABA release in the MS/DBB is altered during the progression of AD. To target HS neurons in a mouse model of AD, we crossed SST-Cre mice to 5XFAD mice and performed stereotaxic injections of Cre-dependent AAV containing mCherry/channelrhodopsin-2 (ChR2) into the hippocampus of offspring at 4, 6, 9, and 12 months. We used optogenetics to selectively stimulate HS terminals while performing whole-cell patch-clamp recordings from MS/DBB neurons in slices. There was a transient reduction in HS-inhibitory postsynaptic current (IPSC) amplitude in female 5XFAD mice at 6 months, but no difference in males at any age, and no difference in paired-pulse ratio in either sex at any age. When bath applying the GABA B R agonist, baclofen, we found a larger decrease in HS-IPSC amplitude in 5XFAD females at 9 months and 5XFAD males at 12 months. In 12-month-old 5XFAD females, response to baclofen was significantly reduced. These data suggest that there is a transient increase in responsiveness to GABA B R activation in 5XFAD mice that occurs earlier in females than in males. These sex-specific changes to HS function are likely to impact the relay of information between the hippocampus and MS/DBB.","journal":"Journal of Molecular Neuroscience","year":2024,"id":452308,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"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":276868,"name":"Jerrel L. Yakel","orcid":"0000-0001-5463-674X","position":1,"is_corresponding":false},{"id":777665,"name":"Joanne C. Damborsky","orcid":null,"position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:02:50.407779Z","pmid":"39212758","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":[]}