Nicotine pretreatment alleviates MK-801-induced behavioral and cognitive deficits in mice by regulating Pdlim5/CRTC1 in the PFC

Qian Wang1, Meng-wei Wang2, Yan-yun Sun2, Xiao-yan Hu1, Pan-pan Geng1, Hui Shu2, Xiao-na Wang2, Hao Wang1, Jun-fang Zhang3,4, Hong-qiang Cheng5, Wei Wang6, Xin-chun Jin1,2
1 Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
2 Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
3 School of Medicine, Ningbo University, Ningbo 315211, China
4 Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo 315211, China
5 Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China
6 Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
Correspondence to: Wei Wang:, Xin-chun Jin:,
DOI: 10.1038/s41401-022-00974-8
Received: 8 April 2022
Accepted: 2 August 2022
Advance online: 29 August 2022


Increasing evidence shows that smoking-obtained nicotine is indicated to improve cognition and mitigate certain symptoms of schizophrenia. In this study, we investigated whether chronic nicotine treatment alleviated MK-801-induced schizophrenia-like symptoms and cognitive impairment in mice. Mice were injected with MK-801 (0.2 mg/kg, i.p.), and the behavioral deficits were assessed using prepulse inhibition (PPI) and T-maze tests. We showed that MK-801 caused cognitive impairment accompanied by increased expression of PDZ and LIM domain 5 (Pdlim5), an adaptor protein that is critically associated with schizophrenia, in the prefrontal cortex (PFC). Pretreatment with nicotine (0.2 mg · kg−1 · d−1, s.c., for 2 weeks) significantly ameliorated MK-801-induced schizophrenia-like symptoms and cognitive impairment by reversing the increased Pdlim5 expression levels in the PFC. In addition, pretreatment with nicotine prevented the MK-801-induced decrease in CREB-regulated transcription coactivator 1 (CRTC1), a coactivator of CREB that plays an important role in cognition. Furthermore, MK-801 neither induced schizophrenia-like behaviors nor decreased CRTC1 levels in the PFC of Pdlim5−/− mice. Overexpression of Pdlim5 in the PFC through intra-PFC infusion of an adreno-associated virus AAV-Pdlim5 induced significant schizophrenia-like symptoms and cognitive impairment. In conclusion, chronic nicotine treatment alleviates schizophrenia-induced memory deficits in mice by regulating Pdlim5 and CRTC1 expression in the PFC.
Keywords: schizophrenia; nicotine; working memory; Pdlim5; CRTC1; prefrontal cortex

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