PMID- 37541362 OWN - NLM STAT- MEDLINE DCOM- 20230921 LR - 20230921 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 956 DP - 2023 Oct 5 TI - Prefrontal cortex-specific Dcc deletion induces schizophrenia-related behavioral phenotypes and fail to be rescued by olanzapine treatment. PG - 175940 LID - S0014-2999(23)00452-1 [pii] LID - 10.1016/j.ejphar.2023.175940 [doi] AB - Multiple genome studies have discovered that variation in deleted in colorectal carcinoma (Dcc) at transcription and translation level were associated with the occurrences of psychiatric disorders. Yet, little is known about the function of Dcc in schizophrenia (SCZ)-related behavioral abnormalities and the efficacy of antipsychotic drugs in vivo. Here, we used an animal model of prefrontal cortex-specific knockdown (KD) of Dcc in adult C57BL/6 mice to study the attention deficits and impaired locomotor activity. Our results supported a critical role of Dcc deletion in SCZ-related behaviors. Notably, olanzapine rescued the SCZ-related behaviors in the MK801-treated mice but not in the cortex-specific Dcc KD mice, indicating that Dcc play a critical in the mechanism of antipsychotic effects of olanzapine. Knockdown of Dcc in prefrontal cortex results in glutamatergic dysfunction, including defects in glutamine synthetase and postsynaptic maturation. As one of the major risk factors of the degree of antipsychotic response, Dcc deletion-induced glutamatergic dysfunction may be involved in the underlying mechanism of treatment resistance of olanzapine. Our findings identified Dcc deletion-mediated SCZ-related behavioral defects, which serve as a valuable animal model for study of SCZ and amenable to targeted investigations in mechanistic hypotheses of the mechanism underlying glutamatergic dysfunction-induced antipsychotic treatment resistance. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Sun, Jing AU - Sun J AD - Neurobiology & Mitochondrial Key Laboratory, Effective & Toxicity Monitoring Innovative Practice Center for Food Pharmaceutical Specialty, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, PR China. Electronic address: sjyancheng@ujs.edu.cn. FAU - Cong, Qijie AU - Cong Q AD - Neurobiology & Mitochondrial Key Laboratory, Effective & Toxicity Monitoring Innovative Practice Center for Food Pharmaceutical Specialty, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, PR China. FAU - Sun, Tingkai AU - Sun T AD - Neurobiology & Mitochondrial Key Laboratory, Effective & Toxicity Monitoring Innovative Practice Center for Food Pharmaceutical Specialty, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, PR China. FAU - Xi, Siyu AU - Xi S AD - Neurobiology & Mitochondrial Key Laboratory, Effective & Toxicity Monitoring Innovative Practice Center for Food Pharmaceutical Specialty, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, PR China. FAU - Liu, Yunxi AU - Liu Y AD - Neurobiology & Mitochondrial Key Laboratory, Effective & Toxicity Monitoring Innovative Practice Center for Food Pharmaceutical Specialty, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, PR China. FAU - Zeng, Rongsen AU - Zeng R AD - Neurobiology & Mitochondrial Key Laboratory, Effective & Toxicity Monitoring Innovative Practice Center for Food Pharmaceutical Specialty, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, PR China. FAU - Wang, Jia AU - Wang J AD - School of Medicine, Jiangsu University, Zhenjiang, 212013, PR China. FAU - Zhang, Weining AU - Zhang W AD - School of Medicine, Jiangsu University, Zhenjiang, 212013, PR China. FAU - Gao, Jing AU - Gao J AD - Neurobiology & Mitochondrial Key Laboratory, Effective & Toxicity Monitoring Innovative Practice Center for Food Pharmaceutical Specialty, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, PR China. FAU - Qian, Jinjun AU - Qian J AD - Department of Neurology, The Fourth People's Hospital of Zhenjiang, Zhenjiang, 212013, PR China. Electronic address: qian-jinjun@163.com. FAU - Qin, Shengying AU - Qin S AD - Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200030, PR China. Electronic address: chinsir@sjtu.edu.cn. LA - eng PT - Journal Article DEP - 20230802 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Antipsychotic Agents) RN - 0 (Dcc protein, mouse) RN - 0 (DCC Receptor) RN - N7U69T4SZR (Olanzapine) SB - IM MH - Animals MH - Mice MH - *Antipsychotic Agents/therapeutic use MH - *DCC Receptor/genetics MH - Mice, Inbred C57BL MH - Olanzapine/pharmacology MH - Phenotype MH - Prefrontal Cortex MH - *Schizophrenia/drug therapy/genetics OTO - NOTNLM OT - Deleted in colorectal carcinoma (Dcc) OT - Glutamatergic dysfunction OT - Olanzapine treatment resistance OT - Schizophrenia (SCZ) COIS- Declaration of competing interest We declared that all authors have personally reviewed and given final approval of the version submitted, neither the manuscript nor its data have been previously published or are currently under consideration for publication. There is none of any conflict of interest, financial or otherwise, related to the submitted work. EDAT- 2023/08/05 05:42 MHDA- 2023/08/31 06:42 CRDT- 2023/08/04 19:13 PHST- 2022/10/20 00:00 [received] PHST- 2023/07/09 00:00 [revised] PHST- 2023/07/31 00:00 [accepted] PHST- 2023/08/31 06:42 [medline] PHST- 2023/08/05 05:42 [pubmed] PHST- 2023/08/04 19:13 [entrez] AID - S0014-2999(23)00452-1 [pii] AID - 10.1016/j.ejphar.2023.175940 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Oct 5;956:175940. doi: 10.1016/j.ejphar.2023.175940. Epub 2023 Aug 2.