Advertisement

Genome-Wide Associations of Schizophrenia Studied with Computer Simulation

  • Samuel A. NeymotinEmail author
  • Nathan S. Kline
  • Mohamed A. Sherif
  • Jeeyune Q. Jung
  • Joseph J. Kabariti
  • William W. Lytton
Chapter
Part of the Springer Series in Computational Neuroscience book series (NEUROSCI)

Abstract

A recent genome-wide association study (GWAS) demonstrated 108 association loci that are associated with development of schizophrenia (Schizophrenia Working Group, 2014). These are just the sites that can be implicated using the statistical power conferred by current data. It is expected that many more sites will be uncovered as new studies use larger numbers of cases and controls. The number of likely associated loci is uncertain, but one estimate suggests it may be in the thousands (International Schizophrenia Consortium). For any given patient, only a small subset of these locations will show mutations. The clinical pathway hypothesis for polygenic diseases predicts that the various sites of damage associated with a given disease reflect sets of mutationally damaged genes that together produce the disease (we will use the term clinical pathway so as to distinguish it from the traditional definition of a pathway as a biochemical sequence) (Sullivan, 2012). What is a clinical pathway? This term remains weakly defined and will differ between diseases and even within a single disease. For example, multiple clinical pathways in schizophrenia may well involve (1) developmental sequences, (2) intracellular cascade sequences such as second-messenger cascades in neurons, (3) genetic activation sequences or RNA transcriptional control sequences, (4) immunological and scavenging pathways (e.g., synapse and cell elimination in schizophrenia Sullivan 2012), and (5) pathways of dynamical physiological interactions that together provide physiological activity.

References

  1. Accili EA, Proenza C, Baruscotti M, DiFrancesco D (2002) From funny current to HCN channels: 20 years of excitation. Physiology 17(1):32–37Google Scholar
  2. Aponte Y, Lien CC, Reisinger E, Jonas P (2006) Hyperpolarization-activated cation channels in fast-spiking interneurons of rat hippocampus. J Physiol 574(1):229–243PubMedPubMedCentralGoogle Scholar
  3. Bender RA, Brewster A, Santoro B, Ludwig A, Hofmann F, Biel M, Baram TZ et al (2001) Differential and age-dependent expression of hyperpolarization-activated, cyclic nucleotide-gated cation channel isoforms 1–4 suggests evolving roles in the developing rat hippocampus. Neuroscience 106(4):689–698PubMedPubMedCentralGoogle Scholar
  4. Börgers C, Kopell N (2003) Synchronization in networks of excitatory and inhibitory neurons with sparse, random connectivity. Neural Comput 15(3):509–538PubMedGoogle Scholar
  5. Brody CD (1999) Correlations without synchrony. Neural Comput 11(7):1537–1551PubMedGoogle Scholar
  6. Buzsáki G, Wang XJ (2012) Mechanisms of gamma oscillations. Annu Rev Neurosci 35:203–225PubMedPubMedCentralGoogle Scholar
  7. Chen S, Wang J, Siegelbaum SA (2001) Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J Gen Physiol 117(5):491–504PubMedPubMedCentralGoogle Scholar
  8. Chover J, Haberly L, Lytton WW (2001) Alternating dominance of NMDA and AMPA for learning and recall: a computer model. Neuroreport 12:2503–2507PubMedGoogle Scholar
  9. Cobb SR, Buhl EH, Halasy K, Paulsen O, Somogyi P (1995) Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 378:75–78Google Scholar
  10. Cull-Candy S, Brickley S, Farrant M (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11(3):327–335PubMedGoogle Scholar
  11. Cutsuridis V, Graham B, Cobb S, Vida I (2010) Hippocampal microcircuits: a computational modeler’s resource book, vol 5. Springer, New YorkGoogle Scholar
  12. de Haan W, van der Flier WM, Wang H, Van Mieghem PFA, Scheltens P, Stam CJ (2012) Disruption of functional brain networks in alzheimer’s disease: what can we learn from graph spectral analysis of resting-state magnetoencephalography? Brain Connect 2(2):45–55PubMedGoogle Scholar
  13. Dumenko VN (2002) Functional significance of high-frequency components of brain electrical activity in the processes of gestalt formation. Zh Vyssh Nerv Deiat Im I P Pavlova 52:539–550PubMedGoogle Scholar
  14. Dyhrfjeld-Johnsen J, Morgan RJ, Földy C, Soltesz I (2008) Upregulated H-Current in hyperexcitable CA1 dendrites after febrile seizures. Front Cell Neurosci 2Google Scholar
  15. Dyhrfjeld-Johnsen J, Morgan RJ, Soltesz I (2009) Double trouble? potential for hyperexcitability following both channelopathic up-and downregulation of Ih in epilepsy. Front Neurosci 3(1):25PubMedPubMedCentralGoogle Scholar
  16. International Schizophrenia Consortium et al, Common polygenic variation contributes to risk of schizophrenia and bipolar disorderGoogle Scholar
  17. Franck N, Duboc C, Sundby C, Amado I, Wykes T, Demily C, Launay C, Le Roy V, Bloch P, Willard D et al (2013) Specific vs general cognitive remediation for executive functioning in schizophrenia: a multicenter randomized trial. Schizophr Res 147:68–74PubMedGoogle Scholar
  18. Fries P, Nikolic D, Singer W (2007) The gamma cycle. Trends Neurosci 30:309–316PubMedGoogle Scholar
  19. Schizophrenia Working Group (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427Google Scholar
  20. Hagiwara N, Irisawa H (1989) Modulation by intracellular Ca2+ of the hyperpolarization-activated inward current in rabbit single sino-atrial node cells. J Physiol 409(1):121–141PubMedPubMedCentralGoogle Scholar
  21. Hasselmo M (2005) Expecting the unexpected: modeling of neuromodulation. Neuron 46:526–528PubMedGoogle Scholar
  22. Hasselmo ME, Bower JM (1992) Cholinergic suppression specific to intrinsic not afferent fiber synapses in rat piriform (olfactory) cortex. J Neurophysiol 67:1222–1229PubMedGoogle Scholar
  23. Hirano Y, Oribe N, Kanba S, Onitsuka T, Nestor PG, Spencer KM (2015) Spontaneous gamma activity in schizophrenia. JAMA Psychiat 72:813–821Google Scholar
  24. Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, Sanislow C, Wang P (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J PsychiatGoogle Scholar
  25. Lazarewicz MT, Ehrlichman RS, Maxwell CR, Gandal MJ, Finkel LH, Siegel SJ (2010) Ketamine modulates theta and gamma oscillations. J Cogn Neurosci 22(7):1452–1464PubMedGoogle Scholar
  26. Lee H, Dvorak D, Fenton AA (2014) Targeting neural synchrony deficits is sufficient to improve cognition in a schizophrenia-related neurodevelopmental model. Front Psychiat 5:15Google Scholar
  27. Lewis DA, Curley AA, Glausier JR, Volk DW (2012) Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 35(1):57–67PubMedGoogle Scholar
  28. Lisman J, Raghavachari S (2006) A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Sci SignalGoogle Scholar
  29. Lisman JE, Idiart MAP (1995) Storage of 7 ± 2 short-term memories in oscillatory subcycles. Science 267:1512–1515PubMedGoogle Scholar
  30. Lytton WW (2008) Computer modelling of epilepsy. Nat Rev Neurosci 9:626–637PubMedPubMedCentralGoogle Scholar
  31. Lytton WW, Sejnowski TJ (1991) Simulations of cortical pyramidal neurons synchronized by inhibitory interneurons. J Neurophysiol 66(3):1059–1079PubMedGoogle Scholar
  32. Lytton WW, Seidenstein AH, Dura-Bernal S, McDougal RA, Schürmann F, Hines ML (in press) Simulation neurotechnologies for advancing brain research: Parallelizing large networks in neuron. Neural ComputGoogle Scholar
  33. Moretti DV, Paternicò D, Binetti G, Zanetti O, Frisoni GB (2013) EEG upper/low alpha frequency power ratio relates to temporo-parietal brain atrophy and memory performances in mild cognitive impairment. Front Aging Neurosci 5:63PubMedPubMedCentralGoogle Scholar
  34. Neymotin SA, Hilscher MM, Moulin TC, Skolnick Y, Lazarewicz MT, Lytton WW (2013) Ih tunes theta/gamma oscillations and cross-frequency coupling in an in silico CA3 model. PLoS One 8:e76285PubMedPubMedCentralGoogle Scholar
  35. Neymotin SA, Jacobs KM, Fenton AA, Lytton WW (2011a) Synaptic information transfer in computer models of neocortical columns. J Comput Neurosci 30(1):69–84PubMedGoogle Scholar
  36. Neymotin SA, Lazarewicz MT, Sherif M, Contreras D, Finkel LH, Lytton WW (2011b) Ketamine disrupts theta modulation of gamma in a computer model of hippocampus. J Neurosci 31(32):11733–11743PubMedPubMedCentralGoogle Scholar
  37. Neymotin SA, McDougal RA, Bulanova AS, Zeki M, Lakatos P, Terman D, Hines ML, Lytton WW (2016) Calcium regulation of HCN channels supports persistent activity in a multiscale model of neocortex. Neurosci 316(1):344–366Google Scholar
  38. Poolos NP, Migliore M, Johnston D (2002) Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 5(8):767–774PubMedGoogle Scholar
  39. Poolos NP, Bullis JB, Roth MK (2006) Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase. J Neurosci 26(30):7995–8003PubMedGoogle Scholar
  40. Santoro B, Baram TZ (2003) The multiple personalities of h-channels. Trends Neurosci 26(10):550–554PubMedPubMedCentralGoogle Scholar
  41. Sekar A, Bialas AR, Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M et al Schizophrenia risk from complex variation of complement component 4. Nature 530:177–183 (2016)PubMedPubMedCentralGoogle Scholar
  42. Serulle Y, Zhang S, Ninan I, Puzzo D, McCarthy M, Khatri L, Arancio O, Ziff EB (2007) A GLuR1-cGKII interaction regulates ampa receptor trafficking. Neuron 56:670–688PubMedPubMedCentralGoogle Scholar
  43. Shannon CE, Weaver W (1949) The mathematical theory of communication. U Illinois Press, UrbanaGoogle Scholar
  44. Silverstein SM, Hatashita-Wong M, Schenkel LS, Wilkniss S, Kovács I, Fehér A, Smith T, Goicochea C, Uhlhaas P, Carpiniello K, Savitz A (2006) Reduced top-down influences in contour detection in schizophrenia. Cogn Neuropsychiatry 11:112–132PubMedGoogle Scholar
  45. Sullivan PF (2012) Puzzling over schizophrenia: schizophrenia as a pathway disease. Nat Med 18:210–211PubMedPubMedCentralGoogle Scholar
  46. Tandon R, Gaebel W, Barch DM, Bustillo J, Gur RE, Heckers S, Malaspina D, Owen MJ, Schultz S, Tsuang M et al (2013) Definition and description of schizophrenia in the DSM-5. Schizophr Res 150:3–10PubMedGoogle Scholar
  47. Tort AB, Rotstein HG, Dugladze T, Gloveli T, Kopell NJ (2007) On the formation of gamma-coherent cell assemblies by oriens lacunosum-moleculare interneurons in the hippocampus. Proc Nat Acad Sci 104:13490–13495PubMedGoogle Scholar
  48. Tost H, Meyer-Lindenberg A (2012) Puzzling over schizophrenia: schizophrenia, social environment and the brain. Nat Med 18:211–213PubMedGoogle Scholar
  49. Uhlhaas PJ, Silverstein SM (2005) Perceptual organization in schizophrenia spectrum disorders: empirical research and theoretical implications. Psychol Bull 131:618–632PubMedGoogle Scholar
  50. Uhlhaas PJ, Singer W (2010) Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci 11(2):100–113PubMedGoogle Scholar
  51. Uhlhaas PJ, Linden DE, Singer W, Haenschel C, Lindner M, Maurer K, and Rodriguez E. (2006a) Dysfunctional long-range coordination of neural activity during gestalt perception in schizophrenia. J Neurosci 26:8168–8175PubMedGoogle Scholar
  52. Uhlhaas PJ, Phillips WA, Mitchell G, Silverstein SM (2006b) Perceptual grouping in disorganized schizophrenia. Psychiatry Res 145:105–117PubMedGoogle Scholar
  53. Uhlhaas PJ, Phillips WA, Schenkel LS, Silverstein SM (2006c) Theory of mind and perceptual context-processing in schizophrenia. Cogn Neuropsychiatry 11:416–436PubMedGoogle Scholar
  54. Uhlhaas PJ, Haenschel C, Nikolić D, Singer W (2008) The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. Schizophr Bull 34(5):927–943PubMedPubMedCentralGoogle Scholar
  55. Wahl-Schott C, Biel M (2009) HCN channels: structure, cellular regulation and physiological function. Cel Mol Life Sci 66(3):470–494Google Scholar
  56. Wang XJ (2002) Pacemaker neurons for the theta rhythm and their synchronization in the septohippocampal reciprocal loop. J Neurophysiol 87(2):889–900PubMedGoogle Scholar
  57. Wang XJ, Buzsaki G (1996) Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. J Neurosci 16(20):6402–6413PubMedGoogle Scholar
  58. White JA, Banks MI, Pearce RA, Kopell NJ (2000) Networks of interneurons with fast and slow γ-aminobutyric acid type A (GABAA) kinetics provide substrate for mixed gamma-theta rhythm. Proc Nat Acad Sci 97(14):8128–8133PubMedGoogle Scholar
  59. Zemankovics R, Káli S, Paulsen O, Freund TF, N Hájos (2010) Differences in subthreshold resonance of hippocampal pyramidal cells and interneurons: the role of h-current and passive membrane characteristics. J Physiol 588(12):2109–2132PubMedPubMedCentralGoogle Scholar
  60. Zong X, Krause S, Chen CC, J Krüger, Gruner C, Cao-Ehlker X, Fenske S, Wahl-Schott C, Biel M (2012) Regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by cCMP. J Biol Chem 287(32):26506–26512PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Samuel A. Neymotin
    • 1
    Email author
  • Nathan S. Kline
    • 2
  • Mohamed A. Sherif
    • 3
    • 4
    • 5
  • Jeeyune Q. Jung
    • 5
  • Joseph J. Kabariti
    • 5
  • William W. Lytton
    • 6
    • 5
  1. 1.Department of NeuroscienceBrown UniversityProvidenceUSA
  2. 2.Institute for Psychiatric ResearchOrangeburgUSA
  3. 3.Yale UniversityNew HavenUSA
  4. 4.VA Connecticut Healthcare SystemWest HavenUSA
  5. 5.Department Physiology and PharmacologySUNY DownstateBrooklynUSA
  6. 6.Department NeurologyKings County Hospital CenterBrooklynUSA

Personalised recommendations