{"doi":"10.1073/pnas.2301312120","title":"Chondroitin 4- <i>O</i> -sulfation regulates hippocampal perineuronal nets and social memory","abstract":"Glycan alterations are associated with aging, neuropsychiatric, and neurodegenerative diseases, although the contributions of specific glycan structures to emotion and cognitive functions remain largely unknown. Here, we used a combination of chemistry and neurobiology to show that 4- O -sulfated chondroitin sulfate (CS) polysaccharides are critical regulators of perineuronal nets (PNNs) and synapse development in the mouse hippocampus, thereby affecting anxiety and cognitive abilities such as social memory. Brain-specific deletion of CS 4- O -sulfation in mice increased PNN densities in the area CA2 (cornu ammonis 2), leading to imbalanced excitatory-to-inhibitory synaptic ratios, reduced CREB activation, elevated anxiety, and social memory dysfunction. The impairments in PNN densities, CREB activity, and social memory were recapitulated by selective ablation of CS 4- O -sulfation in the CA2 region during adulthood. Notably, enzymatic pruning of the excess PNNs reduced anxiety levels and restored social memory, while chemical manipulation of CS 4- O -sulfation levels reversibly modulated PNN densities surrounding hippocampal neurons and the balance of excitatory and inhibitory synapses. These findings reveal key roles for CS 4- O -sulfation in adult brain plasticity, social memory, and anxiety regulation, and they suggest that targeting CS 4- O -sulfation may represent a strategy to address neuropsychiatric and neurodegenerative diseases associated with social cognitive dysfunction.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":321937,"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":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":363254,"name":"Amélie M. Joffrin","orcid":"0000-0002-5810-6073","position":1,"is_corresponding":false},{"id":1034807,"name":"Yuan Zhao","orcid":"0000-0002-7306-5038","position":2,"is_corresponding":false},{"id":1034808,"name":"Gregory M. Miller","orcid":"0009-0005-7397-9277","position":3,"is_corresponding":false},{"id":659647,"name":"Grace C. Zhang","orcid":"0000-0002-2044-9230","position":4,"is_corresponding":false},{"id":259670,"name":"Yuki Oka","orcid":"0000-0003-2686-0677","position":5,"is_corresponding":false},{"id":363255,"name":"Linda C. Hsieh‐Wilson","orcid":"0000-0001-5661-1714","position":6,"is_corresponding":false},{"id":1034806,"name":"Huiqian Huang","orcid":"0000-0002-9989-9532","position":0,"is_corresponding":true}],"reference_count":99,"raw_metadata":null,"created_at":"2026-07-19T01:07:37.596550Z","pmid":"37279269","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":[]}