{"doi":"10.1126/scisignal.adn4556","title":"Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice","abstract":"Signaling mediated by brain-derived neurotrophic factor (BDNF), which is supported by the postsynaptic scaffolding protein PSD-95, has antidepressant effects. Conversely, clinical depression is associated with reduced BDNF signaling. We found that peptidomimetic compounds that bind to PSD-95 promoted signaling by the BDNF receptor TrkB in the hippocampus and reduced depression-like behaviors in mice. The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an α-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB–Gα i1/3 –PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out Gα i1/3 in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95–TrkB complexes have therapeutic potential to alleviate depression.","journal":"Science Signaling","year":2024,"id":418550,"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":49,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"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":1206938,"name":"Xiaozhong Zhou","orcid":"0000-0003-3076-5090","position":1,"is_corresponding":false},{"id":707826,"name":"Gang Chen","orcid":"0000-0002-0758-1907","position":2,"is_corresponding":false},{"id":1206939,"name":"Weifeng Luo","orcid":"0000-0002-3594-1885","position":3,"is_corresponding":false},{"id":1206940,"name":"Chongying Zhou","orcid":"0009-0001-4014-3140","position":4,"is_corresponding":false},{"id":1207727,"name":"Tian-ju He","orcid":null,"position":5,"is_corresponding":false},{"id":303970,"name":"Mandar T. Naik","orcid":"0000-0002-7016-572X","position":6,"is_corresponding":false},{"id":1059552,"name":"Qin Jiang","orcid":"0000-0003-0541-4635","position":7,"is_corresponding":false},{"id":941035,"name":"John Marshall","orcid":"0000-0002-9937-0268","position":8,"is_corresponding":false},{"id":1059553,"name":"Cong Cao","orcid":"0000-0003-0824-3472","position":9,"is_corresponding":false},{"id":1206937,"name":"Xin Shi","orcid":"0000-0003-4902-5498","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T01:57:09.067930Z","pmid":"38687826","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":[]}