Abstract
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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res. 2005;76:135–57.
Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA. Prevalence of smoking among psychiatric outpatients. Am J Psychiatry. 1986;143:993–7.
D’Souza MS, Markou A. Schizophrenia and tobacco smoking comorbidity: nAChR agonists in the treatment of schizophrenia-associated cognitive deficits. Neuropharmacology. 2011;62:1564–73.
Elvevag B, Goldberg TE. Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol. 2000;14:1–21.
McGurk SR, Meltzer HY. The role of cognition in vocational functioning in schizophrenia. Schizophr Res. 2000;45:175–84.
Semenova S, Jin X, McClure-Begley TD, Tadman MP, Marks MJ, Markou A. Differential effects of withdrawal from intermittent and continuous nicotine exposure on reward deficit and somatic aspects of nicotine withdrawal and expression of alpha4beta2* nAChRs in Wistar male rats. Pharmacol Biochem Behav. 2018;171:54–65.
Levin ED, McClernon FJ, Rezvani AH. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl). 2006;184:523–39.
Shu H, Wang M, Song M, Sun Y, Shen X, Zhang J, et al. Acute nicotine treatment alleviates LPS-induced impairment of fear memory reconsolidation through AMPK activation and CRTC1 upregulation in hippocampus. Int J Neuropsychopharmacol. 2020;23:687–99.
Shu H, Zheng GQ, Wang X, Sun Y, Liu Y, Weaver JM, et al. Activation of matrix metalloproteinase in dorsal hippocampus drives improvement in spatial working memory after intra-VTA nicotine infusion in rats. J Neurochem. 2015;135:357–67.
Koukouli F, Rooy M, Tziotis D, Sailor KA, O’Neill HC, Levenga J, et al. Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nat Med. 2017;23:347–54.
Horiuchi Y, Arai M, Niizato K, Iritani S, Noguchi E, Ohtsuki T, et al. A polymorphism in the PDLIM5 gene associated with gene expression and schizophrenia. Biol Psychiatry. 2006;59:434–9.
Zain MA, Roffeei SN, Zainal NZ, Kanagasundram S, Mohamed Z. Nonsynonymous polymorphisms of the PDLIM5 gene association with the occurrence of both bipolar disorder and schizophrenia. Psychiatr Genet. 2013;23:258–61.
Li C, Tao R, Qin W, Zheng Y, He G, Shi Y, et al. Positive association between PDLIM5 and schizophrenia in the Chinese Han population. Int J Neuropsychopharmacol. 2008;11:27–34.
Moselhy H, Eapen V, Akawi NA, Younis A, Salih B, Othman AR, et al. Secondary association of PDLIM5 with paranoid schizophrenia in Emirati patients. Meta Gene. 2015;5:135–9.
Iwamoto K, Kakiuchi C, Bundo M, Ikeda K, Kato T. Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Mol Psychiatry. 2004;9:406–16.
Numata S, Ueno S, Iga J, Yamauchi K, Hongwei S, Hashimoto R, et al. Gene expression in the peripheral leukocytes and association analysis of PDLIM5 gene in schizophrenia. Neurosci Lett. 2007;415:28–33.
Herrick S, Evers DM, Lee JY, Udagawa N, Pak DT. Postsynaptic PDLIM5/Enigma Homolog binds SPAR and causes dendritic spine shrinkage. Mol Cell Neurosci. 2010;43:188–200.
Saura CA, Cardinaux JR. Emerging roles of CREB-regulated transcription coactivators in brain physiology and pathology. Trends Neurosci. 2017;40:720–33.
Xue ZC, Wang C, Wang QW, Zhang JF. CREB-regulated transcription coactivator 1: important roles in neurodegenerative disorders. Sheng Li Xue Bao. 2015;67:155–62.
Breuillaud L, Rossetti C, Meylan EM, Merinat C, Halfon O, Magistretti PJ, et al. Deletion of CREB-regulated transcription coactivator 1 induces pathological aggression, depression-related behaviors, and neuroplasticity genes dysregulation in mice. Biol Psychiatry. 2012;72:528–36.
Csernansky JG, Martin M, Shah R, Bertchume A, Colvin J, Dong H. Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice. Neuropsychopharmacology. 2005;30:2135–43.
van der Staay FJ, Rutten K, Erb C, Blokland A. Effects of the cognition impairer MK-801 on learning and memory in mice and rats. Behav Brain Res. 2011;220:215–29.
Castner SA, Goldman-Rakic PS, Williams GV. Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology (Berl). 2004;174:111–25.
Jentsch JD, Tran A, Le D, Youngren KD, Roth RH. Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacology. 1997;17:92–9.
Cheng H, Kimura K, Peter AK, Cui L, Ouyang K, Shen T, et al. Loss of enigma homolog protein results in dilated cardiomyopathy. Circ Res. 2010;107:348–56.
Park SJ, Lee Y, Oh HK, Lee HE, Ko SY, Kim B, et al. Oleanolic acid attenuates MK-801-induced schizophrenia-like behaviors in mice. Neuropharmacology. 2014;86:49–56.
Shao S, Li M, Du W, Shao F, Wang W. Galanthamine, an acetylcholine inhibitor, prevents prepulse inhibition deficits induced by adolescent social isolation or MK-801 treatment. Brain Res. 2014;1589:105–11.
Chen HH, Stoker A, Markou A. The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice. Psychopharmacology (Berl). 2010;209:343–50.
Shen X, Sun Y, Wang M, Shu H, Zhu LJ, Yan PY, et al. Chronic N-acetylcysteine treatment alleviates acute lipopolysaccharide-induced working memory deficit through upregulating caveolin-1 and synaptophysin in mice. Psychopharmacology (Berl). 2018;235:179–91.
Li C, Tang Y, Yang J, Zhang X, Liu Y, Tang A. Sub-chronic antipsychotic drug administration reverses the expression of neuregulin 1 and ErbB4 in a cultured MK801-induced mouse primary hippocampal neuron or a neurodevelopmental schizophrenia model. Neurochem Res. 2016;41:2049–64.
Naik P, Fofaria N, Prasad S, Sajja RK, Weksler B, Couraud PO, et al. Oxidative and pro-inflammatory impact of regular and denicotinized cigarettes on blood brain barrier endothelial cells: is smoking reduced or nicotine-free products really safe? BMC Neurosci. 2014;15:51.
Liu J, Jin X, Liu KJ, Liu W. Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage. J Neurosci. 2012;32:3044–57.
Chen S, Sun Y, Li F, Zhang X, Hu X, Zhao X, et al. Modulation of alpha7nAchR by melatonin alleviates ischemia and reperfusion-compromised integrity of blood-brain barrier through inhibiting HMGB1-mediated microglia activation and CRTC1-mediated neuronal loss. Cell Mol Neurobiol. 2021. https://doi.org/10.1007/s10571-021-01122-2. online ahead of Print.
Zhang X, Shen X, Dong J, Liu WC, Song M, Sun Y, et al. Inhibition of reactive astrocytes with fluorocitrate ameliorates learning and memory impairment through upregulating CRTC1 and synaptophysin in ischemic stroke rats. Cell Mol Neurobiol. 2019;39:1151–63.
Sun Y, Chen X, Zhang X, Shen X, Wang M, Wang X, et al. β2-Adrenergic receptor-mediated HIF-1alpha upregulation mediates blood brain barrier damage in acute cerebral ischemia. Front Mol Neurosci. 2017;10:257.
Suryavanshi PS, Ugale RR, Yilmazer-Hanke D, Stairs DJ, Dravid SM. GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice. Br J Pharmacol. 2014;171:799–809.
Lainiola M, Procaccini C, Linden AM. mGluR3 knockout mice show a working memory defect and an enhanced response to MK-801 in the T- and Y-maze cognitive tests. Behav Brain Res. 2014;266:94–103.
Nonaka M, Kim R, Fukushima H, Sasaki K, Suzuki K, Okamura M, et al. Region-specific activation of CRTC1-CREB signaling mediates long-term fear memory. Neuron. 2014;84:92–106.
Bang C, Batkai S, Dangwal S, Gupta SK, Foinquinos A, Holzmann A, et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest. 2014;124:2136–46.
Hahn B, Harvey AN, Concheiro-Guisan M, Huestis MA, Holcomb HH, Gold JM. A test of the cognitive self-medication hypothesis of tobacco smoking in schizophrenia. Biol Psychiatry. 2013;74:436–43.
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008;10:1691–715.
Sacco KA, Termine A, Seyal A, Dudas MM, Vessicchio JC, Krishnan-Sarin S, et al. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry. 2005;62:649–59.
Gould TJ, Leach PT. Cellular, molecular, and genetic substrates underlying the impact of nicotine on learning. Neurobiol Learn Mem. 2013;107:108–32.
Waterhouse U, Brennan KA, Ellenbroek BA. Nicotine self-administration reverses cognitive deficits in a rat model for schizophrenia. Addict Biol. 2017.23:620–30.
Waterhouse U, Roper VE, Brennan KA, Ellenbroek BA. Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats. Dis Model Mech. 2016;9:1159–67.
Young JW, Meves JM, Geyer MA. Nicotinic agonist-induced improvement of vigilance in mice in the 5-choice continuous performance test. Behav Brain Res. 2013;240:119–33.
Hambsch B, Keyworth H, Lind J, Otte DM, Racz I, Kitchen I, et al. Chronic nicotine improves short-term memory selectively in a G72 mouse model of schizophrenia. Br J Pharmacol. 2014;171:1758–71.
Cunningham C, Campion S, Teeling J, Felton L, Perry VH. The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C). Brain Behav Immun. 2007;21:490–502.
Wallace TL, Bertrand D. Importance of the nicotinic acetylcholine receptor system in the prefrontal cortex. Biochem Pharmacol. 2013;85:1713–20.
Zhang CL, Aime M, Laheranne E, Houbaert X, El Oussini H, Martin C, et al. Protein kinase A deregulation in the medial prefrontal cortex impairs working memory in murine oligophrenin-1 deficiency. J Neurosci. 2017;37:11114–26.
Senkowski D, Gallinat J. Dysfunctional prefrontal gamma-band oscillations reflect working memory and other cognitive deficits in schizophrenia. Biol Psychiatry. 2015;77:1010–9.
Samsom JN, Wong AH. Schizophrenia and depression co-morbidity: what we have learned from animal models. Front Psychiatry. 2015;6:13.
Miao X, Liu W, Fan B, Lin H. Transcriptomic heterogeneity of Alzheimer’s disease associated with lipid genetic risk. Neuromol Med. 2020;22:534–41.
Lu Y, Jiang J, Si J, Wu Q, Tian F, Jiao K, et al. PDLIM5 improves depression-like behavior of prenatal stress offspring rats via methylation in male, but not female. Psychoneuroendocrinology. 2020;115:104629.
Horiuchi Y, Ishikawa M, Kaito N, Iijima Y, Tanabe Y, Ishiguro H, et al. Experimental evidence for the involvement of PDLIM5 in mood disorders in hetero knockout mice. PLoS One. 2013;8:e59320.
Parra-Damas A, Chen M, Enriquez-Barreto L, Ortega L, Acosta S, Perna JC, et al. CRTC1 function during memory encoding is disrupted in neurodegeneration. Biol Psychiatry. 2016;81:111–23.
Zheutlin AB, Jeffries CD, Perkins DO, Chung Y, Chekroud AM, Addington J, et al. The role of microRNA expression in cortical development during conversion to psychosis. Neuropsychopharmacology. 2017;42:2188–95.
John J, Bhatia T, Kukshal P, Chandna P, Nimgaonkar VL, Deshpande SN, et al. Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition. Schizophrenia Res. 2016;174:29–34.
Strickland ER, Hook MA, Balaraman S, Huie JR, Grau JW, Miranda RC. MicroRNA dysregulation following spinal cord contusion: implications for neural plasticity and repair. Neuroscience. 2011;186:146–60.
Yelamanchili SV, Chaudhuri AD, Chen LN, Xiong H, Fox HS. MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease. Cell Death Dis. 2010;1:e77.
Zhang Y, Pan T, Zhong X, Cheng C. Nicotine upregulates microRNA-21 and promotes TGF-beta-dependent epithelial-mesenchymal transition of esophageal cancer cells. Tumour Biol. 2014;35:7063–72.
Shin VY, Jin H, Ng EK, Cheng AS, Chong WW, Wong CY, et al. NF-kappaB targets miR-16 and miR-21 in gastric cancer: involvement of prostaglandin E receptors. Carcinogenesis. 2011;32:240–5.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (81671145, 81870973, 81701316). We thank Dr Chun-lei Zhang for advice and comments on the paper. We thank Prof Xue-chu Zhen for providing the PPI equipment.
Author information
Authors and Affiliations
Contributions
This work was performed and accomplished by all authors. QW, MWW, YYS, XYH, HS, XNW, and HW contributed to the execution of the entire research project and the statistical analyses. QW, YS, PPG, JFZ, HQC, WW, and XCJ wrote the paper. All authors have read and approved the final paper.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Wang, Q., Wang, Mw., Sun, Yy. et al. Nicotine pretreatment alleviates MK-801-induced behavioral and cognitive deficits in mice by regulating Pdlim5/CRTC1 in the PFC. Acta Pharmacol Sin 44, 780–790 (2023). https://doi.org/10.1038/s41401-022-00974-8
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41401-022-00974-8
