title: Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia.
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.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.|Department of Radiology, University of California, San Diego, La Jolla, CA, USA.|Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.|NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Devor
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: O A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.|NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Mäki-Marttunen
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: O B
authors.initials: OB
authors.lastname: Smeland
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.|Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: C-C
authors.initials: CC
authors.lastname: Fan
authors.affiliation: Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.|Institute of Biological Psychiatry, Medical Health Center, Sct. Hans Hospital and University of Copenhagen, Copenhagen, Denmark.
authors.forename: A J
authors.initials: AJ
authors.lastname: Schork
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Holland
authors.affiliation: Institute of Biological Psychiatry, Medical Health Center, Sct. Hans Hospital and University of Copenhagen, Copenhagen, Denmark.|Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Thompson
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Witoelar
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla, CA, USA.|Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Desikan
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: L K
authors.initials: LK
authors.lastname: McEvoy
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.|NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Djurovic
authors.affiliation: Laboratory for Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Department of Neurology, Karolinska Institute, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Svenningsson
authors.affiliation: Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, Oslo, Norway.|Department of Physics, University of Oslo, Oslo, Norway.
authors.forename: G T
authors.initials: GT
authors.lastname: Einevoll
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.|Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Dale
mesh_terms: D001921:Brain / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020412:Multifactorial Inheritance / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D058468:Receptors, Ionotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D058468:Receptors, Ionotropic Glutamate; D018094:Receptors, Metabotropic Glutamate; D005680:gamma-Aminobutyric Acid; D004298:Dopamine