Current Psychiatry Reports

, Volume 5, Issue 2, pp 155–161 | Cite as

The genetics of sensory gating deficits in schizophrenia

  • Robert Freedman
  • Ann Olincy
  • Randall G. Ross
  • Merilyne C. Waldo
  • Karen E. Stevens
  • Lawrence E. Adler
  • Sherry Leonard


Sensory gating abnormalities are an early clinical symptom of schizophrenia, and are characterized by a decrease in the brain’s normal ability to inhibit the response to unimportant stimuli. Patients appear hypervigilant and have difficulty focusing their attention. A neurobiologic mechanism involved in these difficulties is nicotinic cholinergic modulation of inhibitory neuronal activity in the hippocampus. One measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the alpha-7-nicotinic receptor gene. This site is one of several that have shown evidence for linkage to schizophrenia, as well as to bipolar disorder, across several studies. Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery.


Nicotine Schizophrenia Clozapine Schizophrenia Patient Nicotinic Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Freedman R, Adler LE, Bickford P, et al.: Schizophrenia and nicotinic receptors. Harv Rev Psychiatry 1994, 2:179–192.PubMedGoogle Scholar
  2. 2.
    Freedman R, Coon H, Myles-Worsley M, et al.: Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A 1997, 94:587–592.PubMedCrossRefGoogle Scholar
  3. 3.
    Leonard S, Gault J, Hopkins J, et al.: Promoter variants in the a7 nicotinic acetylcholine receptor subunit gene are associated with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry 2002, In press. This paper describes in detail findings in the promoter region of the gene for the alpha-7-nicotinic receptor and their relationship to the risk for schizophrenia and P50 inhibition.Google Scholar
  4. 4.
    Mirnics K, Middleton FA, Stanwood GD, et al.: Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry 2002, 6:293–301.CrossRefGoogle Scholar
  5. 5.
    Chumakov I, Blumenfeld M, Guerassimenko O, et al.: Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A 2002, 99:13675–13680.PubMedCrossRefGoogle Scholar
  6. 6.
    Egan MF, Goldberg TE, Kolachan BS, et al.: Effect of COMT val 108/158 met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 2001, 98:6917–6922.PubMedCrossRefGoogle Scholar
  7. 7.
    Straub R, Jiang Y, MacLean CJ, et al.: Genetic variation in the 6p22.3 gene DTNBP1, the human orthology of the mouse dysbindin gene is associated with schizophrenia. Am J Hum Genet 20002, 7:337–348. The chromosome 6p locus is one of the most frequently replicated sites for the genetic transmission of schizophrenia. Dysbindin is a promising candidate gene in the area, just as CHRNA7 is a promising gene at chromosome 15q14. Similar progress is being made in identifying polymorphisms associated with the illness in these genes.Google Scholar
  8. 8.
    Adler LE, Pachtman E, Franks R, et al.: Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 1982, 17:639–654.PubMedGoogle Scholar
  9. 9.
    Boutros NN, Zouridakis G, Overall J: Replication and extension of P50 findings in schizophrenia. Clin Electroencephalogr 1991, 22:40–45.PubMedGoogle Scholar
  10. 10.
    Judd LL, McAdams L, Budnick B, Braff DL: Sensory gating deficits in schizophrenia: new results. Am J Psychiatry 1992,149:488–493.PubMedGoogle Scholar
  11. 11.
    Jin Y, Potkin SG, Patterson JV, et al.: Effects of P50 temporal variability on sensory gating in schizophrenia. Psychiatry Res 1997, 70:71–81.PubMedCrossRefGoogle Scholar
  12. 12.
    Clementz BA, Geyer MA, Braff DL: P50 suppression among schizophrenia and normal comparison subjects: a methodological analysis. Biol Psychiatry 1997, 41:1035–1044.PubMedCrossRefGoogle Scholar
  13. 13.
    Yee CM, Nuechterlein KH, Morris SE, White PM: P50 suppression in recent-onset schizophrenia: clinical correlates and risperidone effects. J Abnorm Psychol 1998, 107:691–698.PubMedCrossRefGoogle Scholar
  14. 14.
    Erwin RJ, Turetskty BI, Gur RE: Dissociation of temporal and spatial P50 subcomponent abnormalities in schizophrenia. Schizophrenia Res 1999, 36:254–261.Google Scholar
  15. 15.
    Ghisolfi ES, Prokopiuk AS, Becker J, et al.: The adenosine antagonist theophylline impairs P50 auditory sensory gating in normal subjects. Neuropsychopharmacology 2002, 26:629–637.Google Scholar
  16. 16.
    Clementz BA, Geyer MA, Braff DL: P50 suppression deficits among the relatives of schizophrenia patients. Schizophr Res 1997, 24:232–241.CrossRefGoogle Scholar
  17. 17.
    Cadenhead KS, Light GA, Geyer MA, Braff DL: Sensory gating deficits assessed by the P50 event-related potential in subjects with schizotypal personality disorder. Am J Psychiatry 2000, 157:55–59.PubMedCrossRefGoogle Scholar
  18. 18.
    Cullum CM, Harris JG, Waldo M, et al.: Neurophysiological and neuropsychological evidence for attentional dysfunction in schizophrenia. Schizophr Res 1993,10:131–141.PubMedCrossRefGoogle Scholar
  19. 19.
    Siegel C, Waldo M, Mizner G, et al.: Deficits in sensory gating in schizophrenic patients and their relatives. Arch Gen Psychiatry 1984, 41:607–612.PubMedGoogle Scholar
  20. 20.
    Boutros NN, Gelernter J, Gooding DC, et al.: Sensory gating and psychosis vulnerability in cocaine-dependent individuals: preliminary data. Biol Psychiatry 2002, 51:683–686.PubMedCrossRefGoogle Scholar
  21. 21.
    Goff WR, Williamson PD, VanGilder JC, et al.: Neural origins of long latency evoked potentials recorded from the depth and from the cortical surface of the brain in man. Prog Clin Neurophysiol 1980, 7:126–145.Google Scholar
  22. 22.
    Benes FM, Berretta S: GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001, 25:1–27.PubMedCrossRefGoogle Scholar
  23. 23.
    Freedman R, Hall M, Adler LE, Leonard S: Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 1995, 38:22–33.PubMedCrossRefGoogle Scholar
  24. 24.
    Heckers S: Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 2001, 11:520–528. This paper is an excellent survey of the extensive functional imaging literature in schizophrenia, which shows that diminished hippocampal inhibition that underlies the loss of P50 inhibition can be demonstrated by a wide variety of imaging techniques.PubMedCrossRefGoogle Scholar
  25. 25.
    Cannon TD, Zorrilla LE, Shtasel D, et al.: Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers. Arch Gen Psychiatry 1994, 51:651–661.PubMedGoogle Scholar
  26. 26.
    Suddath RL, Christison GW, Torrey EF, et al.: Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 1990, 322:789–794.PubMedCrossRefGoogle Scholar
  27. 27.
    Seidman LJ, Faraone SV, Goldstein JM, et al.: Left hippocampal volume as a vulnerability indication for schizophrenia: A magnetic resonance imaging morphometric study of nonpsychotic first degree relatives. Arch Gen Psychiatry 2002, 59:839–849. A wide range of endophenotypes are being investigated in schizophrenia to find deficits that are more closely related to a single genetic abnormality than the more complex illness itself. Diminished hippocampal volume and an accompanying decrease in verbal learning ability are serious impediments to psychosocial rehabilitation in schizophrenia, which is shown to be a familial and possibly genetic factor.PubMedCrossRefGoogle Scholar
  28. 28.
    Thompson PM, Vidal C, Giedd JN, et al.: Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci 2001, 98:11650–11655.PubMedCrossRefGoogle Scholar
  29. 29.
    Bickford-Wimer PC, Nagamoto H, Johnson R, et al.: Auditory sensory gating in hippocampal neurons: a model system in the rat. Biol Psychiatry 1990, 27:183–192.PubMedCrossRefGoogle Scholar
  30. 30.
    Luntz-Leybman V, Bickford PC, Freedman R: Cholinergic gating of response to auditory stimuli in rat hippocampus. Brain Res 1992, 587:130–136.PubMedCrossRefGoogle Scholar
  31. 31.
    Stevens KE, Freedman R, Collins AC, et al.: Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains. Neuropsychopharmacology 1996, 15:152–162.PubMedCrossRefGoogle Scholar
  32. 32.
    Leonard S, Gault J, Moore T, et al.: Further investigation of a chromosome 15 locus in schizophrenia: analysis of affected sibling pairs from the National Institute of Mental Health Genetics Initiative. Am J Med Genet 1998, 81:308–312.PubMedCrossRefGoogle Scholar
  33. 33.
    Freedman R, Leonard S, Gault JM, et al.: Linkage dysequilibrium for schizophrenia at the chromosome 15q13–14 locus of the alpha 7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am J Med Genet 2001, 105:20–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Freedman R, Leonard S, Olincy A, et al.: Evidence for the multigenic inheritance of schizophrenia. Am J Med Genet 2000, 105:794–800. This paper describes evidence for inheritance of schizophrenia at the 15q14 locus in relationship to inheritance at a number of other sites. The multigenic nature of schizophrenia means that a number of very common genetic abnormalities, some with frequencies in the general population of over 20%, contribute to the risk for this illness.CrossRefGoogle Scholar
  35. 35.
    Kaufmann CA, Suarez B, Malaspina D, et al.: National Institute of Mental Health Genetics Initiative Millennium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet 1998, 81:282–289.PubMedCrossRefGoogle Scholar
  36. 36.
    Gejman PV, Sanders AR, Badner JA, et al.: Linkage analysis of schizophrenia to chromosome 15. Am J Med Genet 2001, 105:789–793.PubMedCrossRefGoogle Scholar
  37. 37.
    Liu CM, Hwu HG, Lin MW, et al.: Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13–14 in Taiwanese families. Am J Med Genet 2001, 105:658–661.PubMedCrossRefGoogle Scholar
  38. 38.
    Riley BP, Makoff AM, Magudi-Carter M, et al.: Haplotype transmission dysequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families. Am J Med Genet 2000, 96:196–201.PubMedCrossRefGoogle Scholar
  39. 39.
    Stassen HH, Bridler R, Hagele S, et al.: Schizophrenia and smoking: evidence for a common neurobiological basis? Am J Med Genet 2000, 96:173–177.PubMedCrossRefGoogle Scholar
  40. 40.
    Stöber G, Saar K, Ruschendorf F, et al.: Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15. Am J Hum Genet 2000, 67:1201–1207.PubMedGoogle Scholar
  41. 41.
    Tsuang DW Skol AD, Faraone SV, et al.: Examination of genetic linkage of chromosome 15 to schizophrenia in a large veterans affairs cooperative study sample. Am J Med Genet 2001, 105:662–668.PubMedCrossRefGoogle Scholar
  42. 42.
    Xu J, Pato MT, Torre CD, et al.: Evidence of linkage dysequilibrium between the alpha 7-nicotinic receptor gene (CHRNA7 locus and schizophrenia in Azorean families. Am J Med Genet 2001, 105:669–674.PubMedCrossRefGoogle Scholar
  43. 43.
    Curtis L, Blouin JL, Radhakrishna U, et al.: Characterization of a series of anabaseine-derived compounds reveals that the 3–4 dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes. Mol Pharmacol 1995, 47:164–171.Google Scholar
  44. 44.
    DeLisi LE, Shaw SH, Crow TJ, et al.: A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder. Am J Psychiatry 2002,159:803–812.PubMedCrossRefGoogle Scholar
  45. 45.
    Neves-Pereira M, Bassett AS, Honer WG, et al.: No evidence for linkage of the CHRNA7 gene region in Canadian schizophrenia families. Am J Med Genet 1998, 81:361–363.PubMedCrossRefGoogle Scholar
  46. 46.
    Turecki G, Grof P, Grof E, et al.: Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium. Mol Psychiatry 2001, 6:570–578.PubMedCrossRefGoogle Scholar
  47. 47.
    Raux G, Bonnet-Brilhault F, Louchart S, et al.: The -2 bp deletion in exon 6 of the "alpha 7-like" nicotinic receptor subunit gene is a risk factor for the P50 sensory gating deficit. Mol Psychiatry 2002, 7:1006–1011.PubMedCrossRefGoogle Scholar
  48. 48.
    Meyer J, Ortega G, Schraut K, et al.: Exclusion of the neuronal nicotinic acetylcholine receptor alpha-7 subunit gene as a candidate for catatonic schizophrenia in a large family supporting the chromosome 15q13-22 locus. Mol Psychiatry 2002, 7:220–223.PubMedCrossRefGoogle Scholar
  49. 49.
    Leonard S, Freedman R: Recombination in an National Institute of Mental Health Schizophrenia Genetics Initiative family fails to exclude CHRNA7. Mol Psychiatry 2003, In press.Google Scholar
  50. 50.
    Gault J, Robinson M, Berger R, et al.: Genomic organization and partial duplication of the human alpha-7 neuronal nicotinic acetylcholine receptor gene. Genomics 1998, 52:173–185.PubMedCrossRefGoogle Scholar
  51. 51.
    Riley B, Williamson M, Collier D, et al.: A 3-Mb map of a large segmental duplication overlapping the alpha 7-nicotinic acetylcholine receptor gene (CHRNA7) at human 15q13–q14. Genomics 2002, 79:197–209.PubMedCrossRefGoogle Scholar
  52. 52.
    Stitzel JA, Farnham DA, Collins AC: Linkage of strain-specific nicotinic receptor alpha(7) subunit restriction fragment length polymorphisms with levels of alpha-bungarotoxin binding in brain. Mol Brain Res 1996, 43:30–40.PubMedCrossRefGoogle Scholar
  53. 53.
    Court J, Spurden D, Lloyd S, et al.: Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alphabungarotoxin and nicotine binding in the thalamus. J Neurochemistry 1999, 73:1590–1597.CrossRefGoogle Scholar
  54. 54.
    Guan ZZ, Zhang X, Blennow K, Nordberg A: Decreased protein level of nicotinic receptor alpha-7 subunit in the frontal cortex from schizophrenic brain. Neuroreport 1999, 10:1779–1782.PubMedCrossRefGoogle Scholar
  55. 55.
    Marutle A, Zhang X, Court J, et al.: Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia. J Chem Neuroanat 2001, 22:115–126.PubMedCrossRefGoogle Scholar
  56. 56.
    Griffith J, O’Neill JE, Petty F, et al.: Nicotinic receptor desensitization and sensory gating deficits in schizophrenia. Biol Psychiatry 1998, 44:98–106.PubMedCrossRefGoogle Scholar
  57. 57.
    George TP, Vessicchio JC, Termine A, et al.: Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology 2002, 26:75–85.PubMedCrossRefGoogle Scholar
  58. 58.
    Adler LE, Hoffer LD, Griffith J, et al.: Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol Psychiatry 1992, 32:607–616.PubMedCrossRefGoogle Scholar
  59. 59.
    Adler LE, Hoffer LD, Wiser A, Freedman R: Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 1993, 150:1856–1861.PubMedGoogle Scholar
  60. 60.
    Olincy A, Ross RG, Young DA, et al.: Improvement in smooth pursuit eye movements after cigarette smoking in schizophrenic patients. Neuropsychopharmacology 1998, 18:175–185.PubMedCrossRefGoogle Scholar
  61. 61.
    Sherr J, Myers C, Avila M, et al.: The effects of nicotine on specific eye tracking measures in schizophrenia. Biol Psychiatry 2002, 52:721–728.PubMedCrossRefGoogle Scholar
  62. 62.
    Nagamoto HT, Adler LE, Hea RA, et al.: Gating of auditory P50 in schizophrenics: unique effects of clozapine. Biol Psychiatry 1996, 40:181–818.PubMedCrossRefGoogle Scholar
  63. 63.
    Simosky JK, Stevens K, Adler LE, Freedman R: Clozapine improves deficient inhibitory auditory processing in DBA/2 mice via a nicotinic cholinergic mechanism. Psychopharmacology 2002, In press.Google Scholar
  64. 64.
    Simosky JK, Stevens KE, Kem WR, Freedman R: Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice. Biol Psychiatry 2001, 50:493–500.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2003

Authors and Affiliations

  • Robert Freedman
    • 1
  • Ann Olincy
  • Randall G. Ross
  • Merilyne C. Waldo
  • Karen E. Stevens
  • Lawrence E. Adler
  • Sherry Leonard
  1. 1.Departments of Psychiatry and PharmacologyUniversity of Colorado Health Sciences CenterDenverUSA

Personalised recommendations