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Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia

Molecular Psychiatry volume 22, pages 792–801 (2017)Cite this article

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Abstract

The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters—glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids—and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate ‘slow’ (G-protein-coupled receptors) and ‘fast’ (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an ‘associative’ disorder—a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways—and may unify a number of currently competing hypotheses of SCZ pathophysiology.

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Acknowledgements

We gratefully acknowledge support from the NIH (NS057198, EB00790, R01MH111359), the Research Council of Norway (229129, 213837, 223273), the South-East Norway Regional Health Authority (2017-112, 2016-064) and KG Jebsen Stiftelsen (SKGJ-MED‐008).

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Author notes

  1. A Devor and O A Andreassen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    A Devor, Y Wang, C-C Fan, D Holland & A M Dale

  2. Department of Radiology, University of California, San Diego, La Jolla, CA, USA

    A Devor, C-C Fan, R S Desikan, L K McEvoy & A M Dale

  3. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    A Devor

  4. NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    A Devor, O A Andreassen, Y Wang, T Mäki-Marttunen, O B Smeland & A Witoelar

  5. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    O A Andreassen, Y Wang, T Mäki-Marttunen, O B Smeland & A Witoelar

  6. Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA

    A J Schork

  7. Institute of Biological Psychiatry, Medical Health Center, Sct. Hans Hospital and University of Copenhagen, Copenhagen, Denmark

    A J Schork & W K Thompson

  8. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    W K Thompson & C-H Chen

  9. Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA

    R S Desikan

  10. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    S Djurovic

  11. Department of Clinical Science, NORMENT, KG Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway

    S Djurovic

  12. Laboratory for Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA

    P Greengard

  13. Department of Neurology, Karolinska Institute, Stockholm, Sweden

    P Svenningsson

  14. Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, Oslo, Norway

    G T Einevoll

  15. Department of Physics, University of Oslo, Oslo, Norway

    G T Einevoll

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Devor, A., Andreassen, O., Wang, Y. et al. Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia. Mol Psychiatry 22, 792–801 (2017). https://doi.org/10.1038/mp.2017.33

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