{"doi":"10.1016/j.nbd.2022.105772","title":"Reduced d-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia","abstract":"Schizophrenia is a psychiatric disorder that affects over 20 million people globally. Notably, schizophrenia is associated with decreased density of dendritic spines and decreased levels of d-serine, a co-agonist required for opening of the N-methyl-d-aspartate receptor (NMDAR). We hypothesized that lowered d-serine levels associated with schizophrenia would enhance ion flux-independent signaling by the NMDAR, driving destabilization and loss of dendritic spines. We tested our hypothesis using the serine racemase knockout (SRKO) mouse model, which lacks the enzyme for d-serine production. We show that activity-dependent spine growth is impaired in SRKO mice, but can be acutely rescued by exogenous d-serine. Moreover, we find a significant bias of synaptic plasticity toward spine shrinkage in the SRKO mice as compared to wild-type littermates. Notably, we demonstrate that enhanced ion flux-independent signaling through the NMDAR contributes to this bias toward spine destabilization, which is exacerbated by an increase in synaptic NMDARs in hippocampal synapses of SRKO mice. Our results support a model in which lowered d-serine levels associated with schizophrenia enhance ion flux-independent NMDAR signaling and bias toward spine shrinkage and destabilization.","journal":"Neurobiology of Disease","year":2022,"id":250537,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9447,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":819929,"name":"Samuel Petshow","orcid":"0000-0002-7989-3598","position":1,"is_corresponding":false},{"id":783747,"name":"Margarita Anisimova","orcid":"0000-0003-1557-7358","position":2,"is_corresponding":false},{"id":562929,"name":"Eden V. Barragan","orcid":"0000-0002-8972-9804","position":3,"is_corresponding":false},{"id":497917,"name":"J.A. Gray","orcid":"0000-0002-7287-0748","position":4,"is_corresponding":false},{"id":325269,"name":"Ivar S. Stein","orcid":"0009-0006-8894-2781","position":5,"is_corresponding":false},{"id":325272,"name":"Karen Zito","orcid":"0000-0002-0799-0460","position":6,"is_corresponding":false},{"id":327350,"name":"Deborah K. Park","orcid":null,"position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-19T00:24:32.960657Z","pmid":"35605760","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":[]}