{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T08:59:18Z","timestamp":1790585958671,"version":"4.1.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"\n Background<\/jats:title>\n Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but acute molecular responses to clozapine remain incompletely characterized. Social isolation rearing produces schizophrenia-relevant behavioral abnormalities and permits joint evaluation of housing and drug exposure.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To characterize behavioral and prefrontal transcriptomic correlates of an acute clozapine challenge in socially isolated mice, reassess previously prioritized\n Ank3<\/jats:italic>\n and\n Nrxn1<\/jats:italic>\n , and provide external cellular-context hypotheses for candidate genes.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Male C57BL\/6J mice were evaluated in a four-group housing-by-drug design using open-field, novel-object recognition and prepulse-inhibition tests. For a reproducible transcriptome-wide audit, 11 publicly retrievable prefrontal cortex libraries were re-quantified using a factorial DESeq2 model with false-discovery-rate control. Historical pairwise prioritization, network analysis, machine-learning screening, molecular docking and molecular-dynamics simulations were treated as exploratory analyses. Adult wild-type prefrontal cortex single-cell RNA-seq data were used for cellular localization, CellChat analysis and virtual knockout, whereas an embryonic cortical reference was used separately for CellOracle transcription-factor perturbation.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Acute clozapine showed its clearest behavioral effect on isolation-associated hyperlocomotion, whereas recognition memory was not improved and prepulse-inhibition results varied by stimulus intensity. The primary DESeq2 analysis identified 56 housing-by-drug interaction genes at FDR &lt;0.05;\n Lamb2<\/jats:italic>\n was the strongest FDR-supported transcriptomic signal.\n Nrxn1<\/jats:italic>\n showed directionally opposite changes in historical pairwise contrasts but did not reach FDR significance in the factorial model, whereas\n Ank3<\/jats:italic>\n showed no corresponding factorial support. In adult prefrontal cortex single-cell data,\n Lamb2<\/jats:italic>\n was concentrated in endothelial cells, while\n Ank3<\/jats:italic>\n and\n Nrxn1<\/jats:italic>\n were broadly detected in neuronal populations. Virtual\n Ank3<\/jats:italic>\n and\n Nrxn1<\/jats:italic>\n knockout profiles contained 16 and 15 significant non-target genes, respectively, with five shared genes and no significant reciprocal candidate effect. Embryonic CellOracle analyses identified model-dependent upstream transcription-factor sensitivity of\n Ank3<\/jats:italic>\n and\n Nrxn1<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n These findings define selective behavioral and prefrontal transcriptomic correlates of an acute clozapine challenge rather than generalized behavioral rescue or clinical treatment-response prediction.\n Lamb2<\/jats:italic>\n was the strongest FDR-supported signal in the primary model, whereas\n Ank3<\/jats:italic>\n and\n Nrxn1<\/jats:italic>\n remain exploratory computational candidates. The external single-cell and virtual-perturbation analyses provide testable cellular and regulatory hypotheses, not evidence of direct binding, causal regulation or clozapine-induced effects\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fphar.2026.1944363","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T08:40:26Z","timestamp":1790584826000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective behavioral and prefrontal transcriptomic correlates of acute clozapine exposure in socially isolated mice"],"prefix":"10.3389","volume":"17","author":[{"given":"Youzhi","family":"Xu","sequence":"first","affiliation":[{"name":"Capital Medical University Yanjing Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Gao","sequence":"additional","affiliation":[{"name":"Ciqu Community Healthcare Center of Tongzhou District","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Capital Medical University Yanjing Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zishen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Capital Medical University Yanjing Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzhi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Capital Medical University Yanjing Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyue","family":"Huo","sequence":"additional","affiliation":[{"name":"Capital Medical University Yanjing Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nbt.3519","article-title":"Near-optimal probabilistic RNA-seq quantification","volume":"34","author":"Bray","year":"2016","journal-title":"Nat. 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