title: Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study.
abstract: BACKGROUND
  Recent genome-wide association studies have identified a large number of genetic risk factors for schizophrenia (SCZ) featuring ion channels and calcium transporters. For some of these risk factors, independent prior investigations have examined the effects of genetic alterations on the cellular electrical excitability and calcium homeostasis. In the present proof-of-concept study, we harnessed these experimental results for modeling of computational properties on layer V cortical pyramidal cells and identified possible common alterations in behavior across SCZ-related genes.
  
  
  METHODS
  We applied a biophysically detailed multicompartmental model to study the excitability of a layer V pyramidal cell. We reviewed the literature on functional genomics for variants of genes associated with SCZ and used changes in neuron model parameters to represent the effects of these variants.
  
  
  RESULTS
  We present and apply a framework for examining the effects of subtle single nucleotide polymorphisms in ion channel and calcium transporter-encoding genes on neuron excitability. Our analysis indicates that most of the considered SCZ-related genetic variants affect the spiking behavior and intracellular calcium dynamics resulting from summation of inputs across the dendritic tree.
  
  
  CONCLUSIONS
  Our results suggest that alteration in the ability of a single neuron to integrate the inputs and scale its excitability may constitute a fundamental mechanistic contributor to mental disease, alongside the previously proposed deficits in synaptic communication and network behavior.
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Mäki-Marttunen
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Halnes
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Devor
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Aree
authors.initials: A
authors.lastname: Witoelar
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bettella
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Gaute T
authors.initials: GT
authors.lastname: Einevoll
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Norwegian Centre for Mental Disorders Research and KG Jebsen Centre for Psychosis Research (TM-M, AW, FB, YW, OAA), Institute of Clinical Medicine, University of Oslo, Oslo; and Department of Mathematical Sciences and Technology (GH, GTE), Norwegian University of Life Sciences, Ås, Norway; Departments of Neurosciences (AD, YW, AMD) and Radiology (AD, AMD), University of California, San Diego, La Jolla, California; Martinos Center for Biomedical Imaging (AD), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and Division of Mental Health and Addiction (FB, YW, OAA) and Department of Medical Genetics (SD), Oslo University Hospital, Oslo; Norwegian Centre for Mental Disorders Research (SD), KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen; and Department of Physics (GTE), University of Oslo, Oslo, Norway.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
keywords: Biophysical modeling; Functional genomics; Genome-wide association studies; Layer V pyramidal cell; Neuron excitability; Schizophrenia