{"doi":"10.1159/000547800","title":"Developmental Selective GSK3α Inhibition Rescues Working Memory Deficits in a Mouse Model of Schizophrenia Predisposition","abstract":"<p>Introduction: The 22q11.2 deletion syndrome is a genetic disorder characterized by pronounced age-dependent emergence of learning and cognitive deficits, including working memory and anxiety-related symptoms. The deletion confers a 20-fold increased risk of a schizophrenia diagnosis, but there are currently no approved pharmacological therapies for this condition. We have previously shown that treatment with a glycogen synthase kinase 3 (GSK3) paralog-nonselective inhibitor during early postnatal development rescues working memory task acquisition in the Df(16)A+/− mouse model of the 22q11.2 deletion. However, GSK3 paralog-nonselective inhibitors are associated with significant toxicological side effects, limiting their therapeutic potential. Here, we build upon this work by testing a newly developed GSK3α paralog-selective inhibitor with less potential for toxicological challenges. Methods: Using the Df(16)A+/− mouse model, we evaluated the effects of GSK3α inhibition on spatial working memory and approach-avoidance behavior. Results: We found that early postnatal GSK3α inhibition from postnatal day 7 (P7) to P28 restored spatial working memory performance in adult Df(16)A+/− mice under conditions of increased working memory demand. Additionally, we observed heightened exploratory behavior in Df(16)A+/− mice that was reverted to baseline levels by GSK3α inhibition in a genotype-independent manner. Conclusion: Overall, we provide evidence supporting the feasibility and effectiveness of paralog-selective GSK3α inhibition-mediated rescue of cognitive function in a model of altered neurodevelopment. </p>","journal":"Complex Psychiatry","year":2025,"id":583867,"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":0.9583,"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":991329,"name":"Chloe M. Aloimonos","orcid":null,"position":1,"is_corresponding":false},{"id":1240507,"name":"Aleksandra Dagunts","orcid":"0000-0001-9378-8017","position":2,"is_corresponding":false},{"id":264528,"name":"Florence F. Wagner","orcid":"0000-0001-8981-0330","position":3,"is_corresponding":false},{"id":890347,"name":"David A. Kupferschmidt","orcid":"0000-0002-9406-7681","position":4,"is_corresponding":false},{"id":61797,"name":"Joseph A. Gogos","orcid":"0000-0002-7491-4476","position":5,"is_corresponding":false},{"id":533180,"name":"Joshua A. Gordon","orcid":"0000-0002-5488-8266","position":6,"is_corresponding":false},{"id":1496393,"name":"Johannes Passecker","orcid":"0000-0002-4366-2691","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:59:07.970345Z","pmid":"41321713","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":[]}