Nicotine reverses hypofrontality in animal models of addiction and schizophrenia

  • Nature Medicine volume 23, pages 347354 (2017)
  • doi:10.1038/nm.4274
  • Download Citation


The prefrontal cortex (PFC) underlies higher cognitive processes1 that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs2. PFC spontaneous default activity3 is altered in neuropsychiatric disorders4, including schizophrenia5—a disorder that can be accompanied by heavy smoking6. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia7,8. Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits9,10,11, but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Here we show that mice expressing a human α5 SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. The decreased activity observed in α5-SNP-expressing mice resembles the hypofrontality observed in patients with psychiatric disorders, including schizophrenia and addiction5,12. Chronic nicotine administration reversed this hypofrontality, suggesting that administration of nicotine may represent a therapeutic strategy for the treatment of schizophrenia, and a physiological basis for the tendency of patients with schizophrenia to self-medicate by smoking13.

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We would like to thank S. Pons for valuable support and discussions on lentiviral constructs, and M. Soudant for production of lentiviral vectors. We also acknowledge the Pasteur Institute Shared Neuroscience Department imaging facility funded by Ile-de-France Domaine d'Intérêt Majeur (DIM/NeRF). We acknowledge the GENIE Program and the Janelia Research Campus and specifically V. Jayaraman, D.S. Kim, L.L. Looger and K. Svoboda from the GENIE Project, Janelia Research Campus, Howard Hughes Medical Institute for making AAV.Syn.GCaMP6f and AAV.Syn.Flex.GCaMP6f available. Finally, we thank G. Fond and M. Groszer for comments on the manuscript. F.K. is a scholar of the Pasteur Paris University Doctoral Program (PPU) and received a stipend from the Stavros Niarchos Foundation. This work was supported by the CNRS UMR 3571, the Fondation de la Recherche Médicale (FRM grant DPA20140629803), the Agence Nationale de la Recherche (ANR), the Laboratoire d'Excellence BIO-PSY (including salary support to F.K., AAP Fin de Thèse 2015), the program PasteurInnov 2012, the FP7 ERANET program NICO-GENE, Grant Agreement n009 BLANC 20092009BLANC 20, the European Commission FP7 RTD Project HEALTH-2009-Neurocyp.08-202088 Grant 242167, French National Cancer Institute Grant CANCEROPOLE IDF 2016-1-TABAC-01-IP-1 MASKOS (all to U.M.), and NIH grants CA089392 and DA015663 (to J.S.). The laboratories of U.M., B.S.G. and D.A.D. are part of the École des Neurosciences de Paris Ile-de-France RTRA network. U.M. and D.A.D. are members of the Laboratory of Excellence, LabEx BIO-PSY. As such, this work was supported by French state funds managed by the ANR within the Investissements d'Avenir program under reference ANR-11-IDEX-0004-02. B.S.G. is a member of the Laboratory of Excellence, LabEx IEC. B.S.G. acknowledges support from the Russian Academic Excellence Project '5-100'.

Author information


  1. Institut Pasteur, Neurobiologie Intégrative des Systèmes Cholinergiques, Paris, France.

    • Fani Koukouli
    •  & Uwe Maskos
  2. CNRS UMR 3571, Paris, France.

    • Fani Koukouli
    • , Kurt A Sailor
    • , Jean-Pierre Changeux
    • , David A DiGregorio
    •  & Uwe Maskos
  3. Group for Neural Theory, Laboratoire de Neurosciences Cognitives, INSERM Unité 969, Département d'Études Cognitive, École Normale Supérieure, Paris, France.

    • Marie Rooy
    •  & Boris S Gutkin
  4. Institut Pasteur, Structural Bioinformatics Unit, CNRS UMR 3528, Paris, France.

    • Dimitrios Tziotis
    •  & Michael Nilges
  5. Institut Pasteur, Perception and Memory Unit, Paris, France.

    • Kurt A Sailor
  6. Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.

    • Heidi C O'Neill
    • , Josien Levenga
    • , Charles A Hoeffer
    •  & Jerry A Stitzel
  7. Institute for Neuroanatomy, Universitätsmedizin Göttingen, Georg-August-Universität, Göttingen, Germany.

    • Mirko Witte
  8. Centre for Cognition and Decision Making, National Research University Higher School of Economics, Moscow, Russia.

    • Boris S Gutkin
  9. Institut Pasteur, Dynamic Neuronal Imaging Unit, Paris, France.

    • David A DiGregorio


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F.K. and U.M. conceived and designed research. F.K. performed experiments. F.K., K.A.S. and D.A.D. established the imaging technique. F.K., M.R., D.T. and D.A.D. designed the analysis code. F.K. and M.R. analyzed data. H.C.O'N., J.L. and C.A.H. performed behavioral experiments. M.W. contributed the VIP-Cre/tdTomato mice. J.A.S. developed the α5SNP mouse line. M.N., J.-P.C. and B.S.G. provided advice. F.K. wrote the original manuscript, which was reviewed and edited by D.A.D. and U.M. and edited by all other authors. U.M. supervised the research.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Uwe Maskos.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Methods, Supplementary Discussion, Supplementary Tables 1–3 and Supplementary Figures 1–11