Synaptic Dysfunction in Schizophrenia

  • Dong-Min Yin
  • Yong-Jun Chen
  • Anupama Sathyamurthy
  • Wen-Cheng Xiong
  • Lin MeiEmail author
Part of the Advances in Experimental Medicine and Biology book series (volume 970)


Schizophrenia alters basic brain processes of perception, emotion, and judgment to cause hallucinations, delusions, thought disorder, and cognitive deficits. Unlike neurodegeneration diseases that have irreversible neuronal degeneration and death, schizophrenia lacks agreeable pathological hallmarks, which makes it one of the least understood psychiatric disorders. With identification of schizophrenia susceptibility genes, recent studies have begun to shed light on underlying pathological mechanisms. Schizophrenia is believed to result from problems during neural development that lead to improper function of synaptic transmission and plasticity, and in agreement, many of the susceptibility genes encode proteins critical for neural development. Some, however, are also expressed at high levels in adult brain. Here, we will review evidence for altered neurotransmission at glutamatergic, GABAergic, dopaminergic, and cholinergic synapses in schizophrenia and discuss roles of susceptibility genes in neural development as well as in synaptic plasticity and how their malfunction may contribute to pathogenic mechanisms of schizophrenia. We propose that mouse models with precise temporal and spatial control of mutation or overexpression would be useful to delineate schizophrenia pathogenic mechanisms.


Excitatory synaptic transmission Inhibitory synaptic transmission Neuromodulators Schizophrenia Schizophrenia susceptibility genes 


  1. Abe, Y., Namba, H., Zheng, Y., & Nawa, H. (2009). In situ hybridization reveals developmental regulation of ErbB1-4 mRNA expression in mouse midbrain: Implication of ErbB receptors for dopaminergic neurons. Neuroscience, 161, 95–110.PubMedCrossRefGoogle Scholar
  2. Abi-Dargham, A., Gil, R., Krystal, J., Baldwin, R. M., Seibyl, J. P., Bowers, M., van Dyck, C. H., Charney, D. S., Innis, R. B., & Laruelle, M. (1998). Increased striatal dopamine transmission in schizophrenia: Confirmation in a second cohort. The American Journal of Psychiatry, 155, 761–767.PubMedGoogle Scholar
  3. Abi-Dargham, A., Mawlawi, O., Lombardo, I., Gil, R., Martinez, D., Huang, Y., Hwang, D. R., Keilp, J., Kochan, L., Van Heertum, R., et al. (2002). Prefrontal dopamine D1 receptors and working memory in schizophrenia. Journal of Neuroscience, 22, 3708–3719.PubMedGoogle Scholar
  4. Abi-Dargham, A., & Moore, H. (2003). Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. The Neuroscientist, 9, 404–416.PubMedCrossRefGoogle Scholar
  5. Abi-Dargham, A., Rodenhiser, J., Printz, D., Zea-Ponce, Y., Gil, R., Kegeles, L. S., Weiss, R., Cooper, T. B., Mann, J. J., Van Heertum, R. L., et al. (2000). Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 97, 8104–8109.PubMedCrossRefGoogle Scholar
  6. Adler, L. E., Hoffer, L. D., Wiser, A., & Freedman, R. (1993). Normalization of auditory physiology by cigarette smoking in schizophrenic patients. The American Journal of Psychiatry, 150, 1856–1861.PubMedGoogle Scholar
  7. Adler, C. M., Malhotra, A. K., Elman, I., Goldberg, T., Egan, M., Pickar, D., & Breier, A. (1999). Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. The American Journal of Psychiatry, 156, 1646–1649.PubMedGoogle Scholar
  8. Akbarian, S., Kim, J. J., Potkin, S. G., Hagman, J. O., Tafazzoli, A., Bunney, W. E., Jr., & Jones, E. G. (1995). Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Archives of General Psychiatry, 52, 258–266.PubMedCrossRefGoogle Scholar
  9. Akbarian, S., Sucher, N. J., Bradley, D., Tafazzoli, A., Trinh, D., Hetrick, W. P., Potkin, S. G., Sandman, C. A., Bunney, W. E., Jr., & Jones, E. G. (1996). Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. Journal of Neuroscience, 16, 19–30.PubMedGoogle Scholar
  10. Akil, M., Pierri, J. N., Whitehead, R. E., Edgar, C. L., Mohila, C., Sampson, A. R., & Lewis, D. A. (1999). Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. The American Journal of Psychiatry, 156, 1580–1589.PubMedGoogle Scholar
  11. Anagnostaras, S. G., Murphy, G. G., Hamilton, S. E., Mitchell, S. L., Rahnama, N. P., Nathanson, N. M., & Silva, A. J. (2003). Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nature Neuroscience, 6, 51–58.PubMedCrossRefGoogle Scholar
  12. Angrist, B. M., & Gershon, S. (1970). The phenomenology of experimentally induced amphetamine psychosis–preliminary observations. Biological Psychiatry, 2, 95–107.PubMedGoogle Scholar
  13. Anis, N. A., Berry, S. C., Burton, N. R., & Lodge, D. (1983). The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. British Journal of Pharmacology, 79, 565–575.PubMedCrossRefGoogle Scholar
  14. Ascoli, G. A., Alonso-Nanclares, L., Anderson, S. A., Barrionuevo, G., Benavides-Piccione, R., Burkhalter, A., Buzsaki, G., Cauli, B., Defelipe, J., Fairen, A., et al. (2008). Petilla terminology: Nomenclature of features of GABAergic interneurons of the cerebral cortex. Nature Reviews Neuroscience, 9, 557–568.PubMedCrossRefGoogle Scholar
  15. Bakshi, V. P., & Geyer, M. A. (1995). Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. Psychopharmacology, 122, 198–201.PubMedCrossRefGoogle Scholar
  16. Bakshi, V. P., Swerdlow, N. R., & Geyer, M. A. (1994). Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. Journal of Pharmacology and Experimental Therapeutics, 271, 787–794.PubMedGoogle Scholar
  17. Barros, C. S., Calabrese, B., Chamero, P., Roberts, A. J., Korzus, E., Lloyd, K., Stowers, L., Mayford, M., Halpain, S., & Muller, U. (2009). Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proceedings of the National Academy of Sciences of the United States of America, 106, 4507–4512.PubMedCrossRefGoogle Scholar
  18. Bast, T., Zhang, W. N., & Feldon, J. (2001). Hyperactivity, decreased startle reactivity, and disrupted prepulse inhibition following disinhibition of the rat ventral hippocampus by the GABA(A) receptor antagonist picrotoxin. Psychopharmacology, 156, 225–233.PubMedCrossRefGoogle Scholar
  19. Beasley, C. L., & Reynolds, G. P. (1997). Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics. Schizophrenia Research, 24, 349–355.PubMedCrossRefGoogle Scholar
  20. Belforte, J. E., Zsiros, V., Sklar, E. R., Jiang, Z., Yu, G., Li, Y., Quinlan, E. M., & Nakazawa, K. (2010). Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nature Neuroscience, 13, 76–83.PubMedCrossRefGoogle Scholar
  21. Bell, D. S. (1973). The experimental reproduction of amphetamine psychosis. Archives of General Psychiatry, 29, 35–40.PubMedCrossRefGoogle Scholar
  22. Benes, F. M., McSparren, J., Bird, E. D., SanGiovanni, J. P., & Vincent, S. L. (1991). Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Archives of General Psychiatry, 48, 996–1001.PubMedCrossRefGoogle Scholar
  23. Benes, F. M., Vincent, S. L., Alsterberg, G., Bird, E. D., & SanGiovanni, J. P. (1992). Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. Journal of Neuroscience, 12, 924–929.PubMedGoogle Scholar
  24. Bird, E. D., Spokes, E. G., Barnes, J., MacKay, A. V., Iversen, L. L., & Shepherd, M. (1977). Increased brain dopamine and reduced glutamic acid decarboxylase and choline acetyl transferase activity in schizophrenia and related psychoses. Lancet, 2, 1157–1158.PubMedCrossRefGoogle Scholar
  25. Bjarnadottir, M., Misner, D. L., Haverfield-Gross, S., Bruun, S., Helgason, V. G., Stefansson, H., Sigmundsson, A., Firth, D. R., Nielsen, B., Stefansdottir, R., et al. (2007). Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: Differential synaptic function in NRG1+/– knock-outs compared with wild-type mice. Journal of Neuroscience, 27, 4519–4529.PubMedCrossRefGoogle Scholar
  26. Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G., & Deisseroth, K. (2005). Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neuroscience, 8, 1263–1268.PubMedCrossRefGoogle Scholar
  27. Breier, A., Su, T. P., Saunders, R., Carson, R. E., Kolachana, B. S., de Bartolomeis, A., Weinberger, D. R., Weisenfeld, N., Malhotra, A. K., Eckelman, W. C., et al. (1997). Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method. Proceedings of the National Academy of Sciences of the United States of America, 94, 2569–2574.PubMedCrossRefGoogle Scholar
  28. Brinkmann, B. G., Agarwal, A., Sereda, M. W., Garratt, A. N., Muller, T., Wende, H., Stassart, R. M., Nawaz, S., Humml, C., Velanac, V., et al. (2008). Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron, 59, 581–595.PubMedCrossRefGoogle Scholar
  29. Busatto, G. F., Pilowsky, L. S., Costa, D. C., Ell, P. J., David, A. S., Lucey, J. V., & Kerwin, R. W. (1997). Correlation between reduced in vivo benzodiazepine receptor binding and severity of psychotic symptoms in schizophrenia. The American Journal of Psychiatry, 154, 56–63.PubMedGoogle Scholar
  30. Chen, X. W., Feng, Y. Q., Hao, C. J., Guo, X. L., He, X., Zhou, Z. Y., Guo, N., Huang, H. P., Xiong, W., Zheng, H., et al. (2008). DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release. The Journal of Cell Biology, 181, 791–801.PubMedCrossRefGoogle Scholar
  31. Chen, Y., Hancock, M. L., Role, L. W., & Talmage, D. A. (2010a). Intramembranous valine linked to schizophrenia is required for neuregulin 1 regulation of the morphological development of cortical neurons. Journal of Neuroscience, 30, 9199–9208.PubMedGoogle Scholar
  32. Chen, Y. J., Zhang, M., Yin, D. M., Wen, L., Ting, A., Wang, P., Lu, Y. S., Zhu, X. H., Li, S. J., Wu, C. Y., et al. (2010b). ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proceedings of the National Academy of Sciences of the United States of America, 107, 21818–21823.PubMedCrossRefGoogle Scholar
  33. De Keyser, J., Claeys, A., De Backer, J. P., Ebinger, G., Roels, F., & Vauquelin, G. (1988). Autoradiographic localization of D1 and D2 dopamine receptors in the human brain. Neuroscience Letters, 91, 142–147.PubMedCrossRefGoogle Scholar
  34. de Leon, J., Dadvand, M., Canuso, C., White, A. O., Stanilla, J. K., & Simpson, G. M. (1995). Schizophrenia and smoking: An epidemiological survey in a state hospital. The American Journal of Psychiatry, 152, 453–455.PubMedGoogle Scholar
  35. Dracheva, S., Marras, S. A., Elhakem, S. L., Kramer, F. R., Davis, K. L., & Haroutunian, V. (2001). N-methyl-D-aspartic acid receptor expression in the dorsolateral prefrontal cortex of elderly patients with schizophrenia. The American Journal of Psychiatry, 158, 1400–1410.PubMedCrossRefGoogle Scholar
  36. Duan, X., Chang, J. H., Ge, S., Faulkner, R. L., Kim, J. Y., Kitabatake, Y., Liu, X. B., Yang, C. H., Jordan, J. D., Ma, D. K., et al. (2007). Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell, 130, 1146–1158.PubMedCrossRefGoogle Scholar
  37. Eastwood, S. L. (2004). The synaptic pathology of schizophrenia: Is aberrant neurodevelopment and plasticity to blame? International Review of Neurobiology, 59, 47–72.PubMedCrossRefGoogle Scholar
  38. Fauman, B., Aldinger, G., Fauman, M., & Rosen, P. (1976). Psychiatric sequelae of phencyclidine abuse. Clinical Toxicology, 9, 529–538.PubMedCrossRefGoogle Scholar
  39. Faustman, W. O., Bardgett, M., Faull, K. F., Pfefferbaum, A., & Csernansky, J. G. (1999). Cerebrospinal fluid glutamate inversely correlates with positive symptom severity in unmedicated male schizophrenic/schizoaffective patients. Biological Psychiatry, 45, 68–75.PubMedCrossRefGoogle Scholar
  40. Fazzari, P., Paternain, A. V., Valiente, M., Pla, R., Lujan, R., Lloyd, K., Lerma, J., Marin, O., & Rico, B. (2010). Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature, 464, 1376–1380.PubMedCrossRefGoogle Scholar
  41. Forrer, G. R., & Miller, J. J. (1958). Atropine coma: A somatic therapy in psychiatry. The American Journal of Psychiatry, 115, 455–458.PubMedGoogle Scholar
  42. Freedman, R., Coon, H., Myles-Worsley, M., Orr-Urtreger, A., Olincy, A., Davis, A., Polymeropoulos, M., Holik, J., Hopkins, J., Hoff, M., et al. (1997). Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proceedings of the National Academy of Sciences of the United States of America, 94, 587–592.PubMedCrossRefGoogle Scholar
  43. Freedman, R., Hall, M., Adler, L. E., & Leonard, S. (1995). Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biological Psychiatry, 38, 22–33.PubMedCrossRefGoogle Scholar
  44. Gajendran, N., Kapfhammer, J. P., Lain, E., Canepari, M., Vogt, K., Wisden, W., & Brenner, H. R. (2009). Neuregulin signaling is dispensable for NMDA- and GABA(A)-receptor expression in the cerebellum in vivo. Journal of Neuroscience, 29, 2404–2413.PubMedCrossRefGoogle Scholar
  45. Gardner, R., & Connell, P. H. (1972). Amphetamine and other non-opioid drug users attending a special drug dependence clinic. British Medical Journal, 2, 322–325.PubMedCrossRefGoogle Scholar
  46. Garey, L. J., Ong, W. Y., Patel, T. S., Kanani, M., Davis, A., Mortimer, A. M., Barnes, T. R., & Hirsch, S. R. (1998). Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. Journal of Neurology, Neurosurgery & Psychiatry, 65, 446–453.CrossRefGoogle Scholar
  47. Gerfen, C. R. (1992). The neostriatal mosaic: Multiple levels of compartmental organization. Trends in Neurosciences, 15, 133–139.PubMedCrossRefGoogle Scholar
  48. Ghiani, C. A., Starcevic, M., Rodriguez-Fernandez, I. A., Nazarian, R., Cheli, V. T., Chan, L. N., Malvar, J. S., de Vellis, J., Sabatti, C., & Dell’Angelica, E. C. (2010). The dysbindin-containing complex (BLOC-1) in brain: Developmental regulation, interaction with SNARE proteins and role in neurite outgrowth. Molecular Psychiatry, 15, 204–215.CrossRefGoogle Scholar
  49. Glantz, L. A., & Lewis, D. A. (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Archives of General Psychiatry, 57, 65–73.PubMedCrossRefGoogle Scholar
  50. Goff, D. C., Henderson, D. C., & Amico, E. (1992). Cigarette smoking in schizophrenia: Relationship to psychopathology and medication side effects. The American Journal of Psychiatry, 149, 1189–1194.PubMedGoogle Scholar
  51. Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M., & Deisseroth, K. (2009). Optical deconstruction of parkinsonian neural circuitry. Science, 324, 354–359.PubMedCrossRefGoogle Scholar
  52. Grunze, H. C., Rainnie, D. G., Hasselmo, M. E., Barkai, E., Hearn, E. F., McCarley, R. W., & Greene, R. W. (1996). NMDA-dependent modulation of CA1 local circuit inhibition. Journal of Neuroscience, 16, 2034–2043.PubMedGoogle Scholar
  53. Gu, Z., Jiang, Q., Fu, A. K., Ip, N. Y., & Yan, Z. (2005). Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex. Journal of Neuroscience, 25, 4974–4984.PubMedCrossRefGoogle Scholar
  54. Guy, J., Gan, J., Selfridge, J., Cobb, S., & Bird, A. (2007). Reversal of neurological defects in a mouse model of Rett syndrome. Science, 315, 1143–1147.PubMedCrossRefGoogle Scholar
  55. Hahn, C. G., Wang, H. Y., Cho, D. S., Talbot, K., Gur, R. E., Berrettini, W. H., Bakshi, K., Kamins, J., Borgmann-Winter, K. E., Siegel, S. J., et al. (2006). Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nature Medicine, 12, 824–828.PubMedCrossRefGoogle Scholar
  56. Hakak, Y., Walker, J. R., Li, C., Wong, W. H., Davis, K. L., Buxbaum, J. D., Haroutunian, V., & Fienberg, A. A. (2001). Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 98, 4746–4751.PubMedCrossRefGoogle Scholar
  57. Hall, H., Sedvall, G., Magnusson, O., Kopp, J., Halldin, C., & Farde, L. (1994). Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain. Neuropsychopharmacol, 11, 245–256.CrossRefGoogle Scholar
  58. Hamera, E., Schneider, J. K., & Deviney, S. (1995). Alcohol, cannabis, nicotine, and caffeine use and symptom distress in schizophrenia. The Journal of Nervous and Mental Disease, 183, 559–565.PubMedCrossRefGoogle Scholar
  59. Hanada, S., Mita, T., Nishino, N., & Tanaka, C. (1987). [3H]muscimol binding sites increased in autopsied brains of chronic schizophrenics. Life Sciences, 40, 259–266.PubMedCrossRefGoogle Scholar
  60. Hancock, M. L., Canetta, S. E., Role, L. W., & Talmage, D. A. (2008). Presynaptic type III neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons. The Journal of Cell Biology, 181, 511–521.PubMedCrossRefGoogle Scholar
  61. Hashimoto, R., Straub, R. E., Weickert, C. S., Hyde, T. M., Kleinman, J. E., & Weinberger, D. R. (2004). Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Molecular Psychiatry, 9, 299–307.PubMedCrossRefGoogle Scholar
  62. Hashimoto, T., Volk, D. W., Eggan, S. M., Mirnics, K., Pierri, J. N., Sun, Z., Sampson, A. R., & Lewis, D. A. (2003). Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. Journal of Neuroscience, 23, 6315–6326.PubMedGoogle Scholar
  63. Hayashi, S., & McMahon, A. P. (2002). Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: A tool for temporally regulated gene activation/inactivation in the mouse. Developmental Biology, 244, 305–318.PubMedCrossRefGoogle Scholar
  64. Hirvonen, M., Laakso, A., Nagren, K., Rinne, J. O., Pohjalainen, T., & Hietala, J. (2004). C957T polymorphism of the dopamine D2 receptor (DRD2) gene affects striatal DRD2 availability in vivo. Molecular Psychiatry, 9, 1060–1061.PubMedCrossRefGoogle Scholar
  65. Hirvonen, J., van Erp, T. G., Huttunen, J., Aalto, S., Nagren, K., Huttunen, M., Lonnqvist, J., Kaprio, J., Hietala, J., & Cannon, T. D. (2005). Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia. Archives of General Psychiatry, 62, 371–378.PubMedCrossRefGoogle Scholar
  66. Holt, D. J., Bachus, S. E., Hyde, T. M., Wittie, M., Herman, M. M., Vangel, M., Saper, C. B., & Kleinman, J. E. (2005). Reduced density of cholinergic interneurons in the ventral striatum in schizophrenia: An in situ hybridization study. Biological Psychiatry, 58, 408–416.PubMedCrossRefGoogle Scholar
  67. Holt, D. J., Herman, M. M., Hyde, T. M., Kleinman, J. E., Sinton, C. M., German, D. C., Hersh, L. B., Graybiel, A. M., & Saper, C. B. (1999). Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia. Neuroscience, 94, 21–31.PubMedCrossRefGoogle Scholar
  68. Howes, O. D., Smith, S., Gaughran, F. P., Amiel, S. A., Murray, R. M., & Pilowsky, L. S. (2006). The relationship between prolactin levels and glucose homeostasis in antipsychotic-treated schizophrenic patients. Journal of Clinical Psychopharmacology, 26, 629–631.PubMedCrossRefGoogle Scholar
  69. Huang, Y. Z., Won, S., Ali, D. W., Wang, Q., Tanowitz, M., Du, Q. S., Pelkey, K. A., Yang, D. J., Xiong, W. C., Salter, M. W., et al. (2000). Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron, 26, 443–455.PubMedCrossRefGoogle Scholar
  70. Iyengar, S. S., & Mott, D. D. (2008). Neuregulin blocks synaptic strengthening after epileptiform activity in the rat hippocampus. Brain Research, 1208, 67–73.PubMedCrossRefGoogle Scholar
  71. Jentsch, J. D., Tran, A., Le, D., Youngren, K. D., & Roth, R. H. (1997). Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacol, 17, 92–99.CrossRefGoogle Scholar
  72. Jentsch, J. D., Trantham-Davidson, H., Jairl, C., Tinsley, M., Cannon, T. D., & Lavin, A. (2009). Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. Neuropsychopharmacol, 34, 2601–2608.CrossRefGoogle Scholar
  73. Kamiya, A., Kubo, K., Tomoda, T., Takaki, M., Youn, R., Ozeki, Y., Sawamura, N., Park, U., Kudo, C., Okawa, M., et al. (2005). A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nature Cell Biology, 7, 1167–1178.PubMedCrossRefGoogle Scholar
  74. Kamiya, A., Tan, P. L., Kubo, K., Engelhard, C., Ishizuka, K., Kubo, A., Tsukita, S., Pulver, A. E., Nakajima, K., Cascella, N. G., et al. (2008). Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: A candidate for psychiatric illnesses. Archives of General Psychiatry, 65, 996–1006.PubMedCrossRefGoogle Scholar
  75. Karlsgodt, K. H., Robleto, K., Trantham-Davidson, H., Jairl, C., Cannon, T. D., Lavin, A., & Jentsch, J. D. (2011). Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance. Biological Psychiatry, 69, 28–34.PubMedCrossRefGoogle Scholar
  76. Kato, T., Abe, Y., Sotoyama, H., Kakita, A., Kominami, R., Hirokawa, S., Ozaki, M., Takahashi, H., & Nawa, H. (2010). Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: Implication in neurodevelopmental hypothesis for schizophrenia. Molecular Psychiatry, 16, 307–320.PubMedCrossRefGoogle Scholar
  77. Kellendonk, C., Simpson, E. H., Polan, H. J., Malleret, G., Vronskaya, S., Winiger, V., Moore, H., & Kandel, E. R. (2006). Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron, 49, 603–615.PubMedCrossRefGoogle Scholar
  78. Keverne, E. B. (1999). GABA-ergic neurons and the neurobiology of schizophrenia and other psychoses. Brain Research Bulletin, 48, 467–473.PubMedCrossRefGoogle Scholar
  79. Kim, J. S., Kornhuber, H. H., Schmid-Burgk, W., & Holzmuller, B. (1980). Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neuroscience Letters, 20, 379–382.PubMedCrossRefGoogle Scholar
  80. Kirkpatrick, B., Xu, L., Cascella, N., Ozeki, Y., Sawa, A., & Roberts, R. C. (2006). DISC1 immunoreactivity at the light and ultrastructural level in the human neocortex. The Journal of Comparative Neurology, 497, 436–450.PubMedCrossRefGoogle Scholar
  81. Kirov, G., Ivanov, D., Williams, N. M., Preece, A., Nikolov, I., Milev, R., Koleva, S., Dimitrova, A., Toncheva, D., O’Donovan, M. C., et al. (2004). Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria. Biological Psychiatry, 55, 971–975.PubMedCrossRefGoogle Scholar
  82. Korotkova, T., Fuchs, E. C., Ponomarenko, A., von Engelhardt, J., & Monyer, H. (2010). NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron, 68, 557–569.PubMedCrossRefGoogle Scholar
  83. Kristiansen, L. V., Beneyto, M., Haroutunian, V., & Meador-Woodruff, J. H. (2006). Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia. Molecular Psychiatry, 11, 705.CrossRefGoogle Scholar
  84. Krystal, J. H., Karper, L. P., Seibyl, J. P., Freeman, G. K., Delaney, R., Bremner, J. D., Heninger, G. R., Bowers, M. B., Jr., & Charney, D. S. (1994). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of General Psychiatry, 51, 199–214.PubMedCrossRefGoogle Scholar
  85. Kucinski, A. J., Stachowiak, M. K., Wersinger, S. R., Lippiello, P. M., & Bencherif, M. (2010). Alpha7 neuronal nicotinic receptors as targets for novel therapies to treat multiple domains of schizophrenia. Current Pharmaceutical Biotechnology, 12, 437–448.CrossRefGoogle Scholar
  86. Kvajo, M., McKellar, H., Arguello, P. A., Drew, L. J., Moore, H., MacDermott, A. B., Karayiorgou, M., & Gogos, J. A. (2008). A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proceedings of the National Academy of Sciences of the United States of America, 105, 7076–7081.PubMedCrossRefGoogle Scholar
  87. Kwon, O. B., Paredes, D., Gonzalez, C. M., Neddens, J., Hernandez, L., Vullhorst, D., & Buonanno, A. (2008). Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. Proceedings of the National Academy of Sciences of the United States of America, 105, 15587–15592.PubMedCrossRefGoogle Scholar
  88. Lacroix, L., Spinelli, S., Broersen, L. M., & Feldon, J. (2000). Blockade of latent inhibition following pharmacological increase or decrease of GABA(A) transmission. Pharmacology, Biochemistry, and Behavior, 66, 893–901.PubMedCrossRefGoogle Scholar
  89. Lahti, A. C., Koffel, B., LaPorte, D., & Tamminga, C. A. (1995). Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacol, 13, 9–19.CrossRefGoogle Scholar
  90. Lahti, A. C., Weiler, M. A., Tamara Michaelidis, B. A., Parwani, A., & Tamminga, C. A. (2001). Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacol, 25, 455–467.CrossRefGoogle Scholar
  91. Lai, C., & Lemke, G. (1991). An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system. Neuron, 6, 691–704.PubMedCrossRefGoogle Scholar
  92. Laruelle, M., Abi-Dargham, A., Gil, R., Kegeles, L., & Innis, R. (1999). Increased dopamine transmission in schizophrenia: Relationship to illness phases. Biological Psychiatry, 46, 56–72.PubMedCrossRefGoogle Scholar
  93. Laruelle, M., Abi-Dargham, A., van Dyck, C. H., Gil, R., D’Souza, C. D., Erdos, J., McCance, E., Rosenblatt, W., Fingado, C., Zoghbi, S. S., et al. (1996). Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proceedings of the National Academy of Sciences of the United States of America, 93, 9235–9240.PubMedCrossRefGoogle Scholar
  94. Law, A. J., Kleinman, J. E., Weinberger, D. R., & Weickert, C. S. (2007). Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Human Molecular Genetics, 16, 129–141.PubMedCrossRefGoogle Scholar
  95. Law, A. J., Lipska, B. K., Weickert, C. S., Hyde, T. M., Straub, R. E., Hashimoto, R., Harrison, P. J., Kleinman, J. E., & Weinberger, D. R. (2006). Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proceedings of the National Academy of Sciences of the United States of America, 103, 6747–6752.PubMedCrossRefGoogle Scholar
  96. Lawford, B. R., Young, R. M., Swagell, C. D., Barnes, M., Burton, S. C., Ward, W. K., Heslop, K. R., Shadforth, S., van Daal, A., & Morris, C. P. (2005). The C/C genotype of the C957T polymorphism of the dopamine D2 receptor is associated with schizophrenia. Schizophrenia Research, 73, 31–37.PubMedCrossRefGoogle Scholar
  97. Lewis, D. A., Pierri, J. N., Volk, D. W., Melchitzky, D. S., & Woo, T. U. (1999). Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biological Psychiatry, 46, 616–626.PubMedCrossRefGoogle Scholar
  98. Li, B., Woo, R. S., Mei, L., & Malinow, R. (2007). The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron, 54, 583–597.PubMedCrossRefGoogle Scholar
  99. Li, W., Zhang, Q., Oiso, N., Novak, E. K., Gautam, R., O’Brien, E. P., Tinsley, C. L., Blake, D. J., Spritz, R. A., Copeland, N. G., et al. (2003). Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nature Genetics, 35, 84–89.PubMedCrossRefGoogle Scholar
  100. Lieberman, J. A., Kane, J. M., & Alvir, J. (1987). Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology, 91, 415–433.PubMedCrossRefGoogle Scholar
  101. Liu, Y., Ford, B., Mann, M. A., & Fischbach, G. D. (2001). Neuregulins increase alpha7 nicotinic acetylcholine receptors and enhance excitatory synaptic transmission in GABAergic interneurons of the hippocampus. Journal of Neuroscience, 21, 5660–5669.PubMedGoogle Scholar
  102. Lohr, J. B., & Flynn, K. (1992). Smoking and schizophrenia. Schizophrenia Research, 8, 93–102.PubMedCrossRefGoogle Scholar
  103. Luby, E. D., Cohen, B. D., Rosenbaum, G., Gottlieb, J. S., & Kelley, R. (1959). Study of a new schizophrenomimetic drug: Sernyl. American Medical Association: Archives of Neurological Psychiatry, 81, 363–369.CrossRefGoogle Scholar
  104. Malhotra, A. K., Pinals, D. A., Adler, C. M., Elman, I., Clifton, A., Pickar, D., & Breier, A. (1997). Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology, 17, 141–150.PubMedCrossRefGoogle Scholar
  105. Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C. (2004). Interneurons of the neocortical inhibitory system. Nature Reviews Neuroscience, 5, 793–807.PubMedCrossRefGoogle Scholar
  106. Marutle, A., Zhang, X., Court, J., Piggott, M., Johnson, M., Perry, R., Perry, E., & Nordberg, A. (2001). Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia. Journal of Chemical Neuroanatomy, 22, 115–126.PubMedCrossRefGoogle Scholar
  107. Mathew, S. V., Law, A. J., Lipska, B. K., Davila-Garcia, M. I., Zamora, E. D., Mitkus, S. N., Vakkalanka, R., Straub, R. E., Weinberger, D. R., Kleinman, J. E., et al. (2007). Alpha7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin 1. Human Molecular Genetics, 16, 2921–2932.PubMedCrossRefGoogle Scholar
  108. Mayford, M., Bach, M. E., Huang, Y. Y., Wang, L., Hawkins, R. D., & Kandel, E. R. (1996). Control of memory formation through regulated expression of a CaMKII transgene. Science, 274, 1678–1683.PubMedCrossRefGoogle Scholar
  109. McBain, C. J., & Kauer, J. A. (2009). Presynaptic plasticity: Targeted control of inhibitory networks. Current Opinion in Neurobiology, 19, 254–262.PubMedCrossRefGoogle Scholar
  110. McCullumsmith, R. E., Clinton, S. M., & Meador-Woodruff, J. H. (2004). Schizophrenia as a disorder of neuroplasticity. International Review of Neurobiology, 59, 19–45.PubMedCrossRefGoogle Scholar
  111. Mei, L., & Xiong, W. C. (2008). Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nature Reviews Neuroscience, 9, 437–452.PubMedCrossRefGoogle Scholar
  112. Mercuri, N. B., Saiardi, A., Bonci, A., Picetti, R., Calabresi, P., Bernardi, G., & Borrelli, E. (1997). Loss of autoreceptor function in dopaminergic neurons from dopamine D2 receptor deficient mice. Neuroscience, 79, 323–327.PubMedCrossRefGoogle Scholar
  113. Mexal, S., Berger, R., Logel, J., Ross, R. G., Freedman, R., & Leonard, S. (2010). Differential regulation of alpha7 nicotinic receptor gene (CHRNA7) expression in schizophrenic smokers. Journal of Molecular Neuroscience, 40, 185–195.PubMedCrossRefGoogle Scholar
  114. Millar, J. K., Christie, S., & Porteous, D. J. (2003). Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochemical and Biophysical Research Communications, 311, 1019–1025.PubMedCrossRefGoogle Scholar
  115. Millar, J. K., Pickard, B. S., Mackie, S., James, R., Christie, S., Buchanan, S. R., Malloy, M. P., Chubb, J. E., Huston, E., Baillie, G. S., et al. (2005). DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science, 310, 1187–1191.PubMedCrossRefGoogle Scholar
  116. Millar, J. K., Wilson-Annan, J. C., Anderson, S., Christie, S., Taylor, M. S., Semple, C. A., Devon, R. S., St Clair, D. M., Muir, W. J., Blackwood, D. H., et al. (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Human Molecular Genetics, 9, 1415–1423.PubMedCrossRefGoogle Scholar
  117. Mirnics, K., Middleton, F. A., Lewis, D. A., & Levitt, P. (2001). Analysis of complex brain disorders with gene expression microarrays: Schizophrenia as a disease of the synapse. Trends in Neurosciences, 24, 479–486.PubMedCrossRefGoogle Scholar
  118. Mirnics, K., Middleton, F. A., Marquez, A., Lewis, D. A., & Levitt, P. (2000). Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron, 28, 53–67.PubMedCrossRefGoogle Scholar
  119. Miyakawa, T., Yamada, M., Duttaroy, A., & Wess, J. (2001). Hyperactivity and intact hippocampus-dependent learning in mice lacking the M1 muscarinic acetylcholine receptor. Journal of Neuroscience, 21, 5239–5250.PubMedGoogle Scholar
  120. Miyoshi, K., Honda, A., Baba, K., Taniguchi, M., Oono, K., Fujita, T., Kuroda, S., Katayama, T., & Tohyama, M. (2003). Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Molecular Psychiatry, 8, 685–694.PubMedCrossRefGoogle Scholar
  121. Moghaddam, B., & Adams, B. W. (1998). Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science, 281, 1349–1352.PubMedCrossRefGoogle Scholar
  122. Mohn, A. R., Gainetdinov, R. R., Caron, M. G., & Koller, B. H. (1999). Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell, 98, 427–436.PubMedCrossRefGoogle Scholar
  123. Morris, J. A., Kandpal, G., Ma, L., & Austin, C. P. (2003). DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: Regulation and loss of interaction with mutation. Human Molecular Genetics, 12, 1591–1608.PubMedCrossRefGoogle Scholar
  124. Mrzljak, L., Levey, A. I., & Goldman-Rakic, P. S. (1993). Association of m1 and m2 muscarinic receptor proteins with asymmetric synapses in the primate cerebral cortex: Morphological evidence for cholinergic modulation of excitatory neurotransmission. Proceedings of the National Academy of Sciences of the United States of America, 90, 5194–5198.PubMedCrossRefGoogle Scholar
  125. Nabeshima, T., Yamada, K., Yamaguchi, K., Hiramatsu, M., Furukawa, H., & Kameyama, T. (1983). Effect of lesions in the striatum, nucleus accumbens and medial raphe on phencyclidine-induced stereotyped behaviors and hyperactivity in rats. European Journal of Pharmacology, 91, 455–462.PubMedCrossRefGoogle Scholar
  126. Nason, M. W., Jr., Adhikari, A., Bozinoski, M., Gordon, J. A., & Role, L. W. (2011). Disrupted activity in the hippocampal-accumbens circuit of type III neuregulin 1 mutant mice. Neuropsychopharmacology, 36, 488–496.PubMedCrossRefGoogle Scholar
  127. Neubauer, H., Adams, M., & Redfern, P. (1975). The role of central cholinergic mechanisms in schizophrenia. Medical Hypotheses, 1, 32–34.PubMedCrossRefGoogle Scholar
  128. Nicodemus, K. K., Luna, A., Vakkalanka, R., Goldberg, T., Egan, M., Straub, R. E., & Weinberger, D. R. (2006). Further evidence for association between ErbB4 and schizophrenia and influence on cognitive intermediate phenotypes in healthy controls. Molecular Psychiatry, 11, 1062–1065.PubMedCrossRefGoogle Scholar
  129. Nikolaus, S., Antke, C., & Muller, H. W. (2009). In vivo imaging of synaptic function in the central nervous system: I. Movement disorders and dementia. Behavioural Brain Research, 204, 1–31.PubMedCrossRefGoogle Scholar
  130. Norton, N., Moskvina, V., Morris, D. W., Bray, N. J., Zammit, S., Williams, N. M., Williams, H. J., Preece, A. C., Dwyer, S., Wilkinson, J. C., et al. (2006). Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia. American Journal of Medical Genetics B: Neuropsychiatric Genetics, 141B, 96–101.CrossRefGoogle Scholar
  131. Numakawa, T., Yagasaki, Y., Ishimoto, T., Okada, T., Suzuki, T., Iwata, N., Ozaki, N., Taguchi, T., Tatsumi, M., Kamijima, K., et al. (2004). Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Human Molecular Genetics, 13, 2699–2708.PubMedCrossRefGoogle Scholar
  132. Okubo, Y., Suhara, T., Suzuki, K., Kobayashi, K., Inoue, O., Terasaki, O., Someya, Y., Sassa, T., Sudo, Y., Matsushima, E., et al. (1997). Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature, 385, 634–636.PubMedCrossRefGoogle Scholar
  133. Olincy, A., Ross, R. G., Young, D. A., Roath, M., & Freedman, R. (1998). Improvement in smooth pursuit eye movements after cigarette smoking in schizophrenic patients. Neuropsychopharmacol, 18, 175–185.CrossRefGoogle Scholar
  134. Ozeki, Y., Tomoda, T., Kleiderlein, J., Kamiya, A., Bord, L., Fujii, K., Okawa, M., Yamada, N., Hatten, M. E., Snyder, S. H., et al. (2003). Disrupted-in-Schizophrenia-1 (DISC-1): Mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proceedings of the National Academy of Sciences of the United States of America, 100, 289–294.PubMedCrossRefGoogle Scholar
  135. Paterson, D., & Nordberg, A. (2000). Neuronal nicotinic receptors in the human brain. Progress in Neurobiology, 61, 75–111.PubMedCrossRefGoogle Scholar
  136. Paylor, R., Nguyen, M., Crawley, J. N., Patrick, J., Beaudet, A., & Orr-Urtreger, A. (1998). Alpha7 nicotinic receptor subunits are not necessary for hippocampal-dependent learning or sensorimotor gating: A behavioral characterization of Acra7-deficient mice. Learning and Memory, 5, 302–316.PubMedGoogle Scholar
  137. Petreanu, L., Mao, T., Sternson, S. M., & Svoboda, K. (2009). The subcellular organization of neocortical excitatory connections. Nature, 457, 1142–1145.PubMedCrossRefGoogle Scholar
  138. Reynolds, G. P., Czudek, C., & Andrews, H. B. (1990). Deficit and hemispheric asymmetry of GABA uptake sites in the hippocampus in schizophrenia. Biological Psychiatry, 27, 1038–1044.PubMedCrossRefGoogle Scholar
  139. Rouge-Pont, F., Usiello, A., Benoit-Marand, M., Gonon, F., Piazza, P. V., & Borrelli, E. (2002). Changes in extracellular dopamine induced by morphine and cocaine: Crucial control by D2 receptors. Journal of Neuroscience, 22, 3293–3301.PubMedGoogle Scholar
  140. Sams-Dodd, F. (1995). Automation of the social interaction test by a video-tracking system: Behavioural effects of repeated phencyclidine treatment. Journal of Neuroscience Methods, 59, 157–167.PubMedCrossRefGoogle Scholar
  141. Sams-Dodd, F. (1996). Phencyclidine-induced stereotyped behaviour and social isolation in rats: A possible animal model of schizophrenia. Behavioural Pharmacology, 7, 3–23.PubMedGoogle Scholar
  142. Sandrock, A. W., Jr., Dryer, S. E., Rosen, K. M., Gozani, S. N., Kramer, R., Theill, L. E., & Fischbach, G. D. (1997). Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science, 276, 599–603.PubMedCrossRefGoogle Scholar
  143. Sawaguchi, T. (2001). The effects of dopamine and its antagonists on directional delay-period activity of prefrontal neurons in monkeys during an oculomotor delayed-response task. Neuroscience Research, 41, 115–128.PubMedCrossRefGoogle Scholar
  144. Sawaguchi, T., & Goldman-Rakic, P. S. (1991). D1 dopamine receptors in prefrontal cortex: Involvement in working memory. Science, 251, 947–950.PubMedCrossRefGoogle Scholar
  145. Sawaguchi, T., & Goldman-Rakic, P. S. (1994). The role of D1-dopamine receptor in working memory: Local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. Journal of Neurophysiology, 71, 515–528.PubMedGoogle Scholar
  146. Scarr, E., Cowie, T. F., Kanellakis, S., Sundram, S., Pantelis, C., & Dean, B. (2009). Decreased cortical muscarinic receptors define a subgroup of subjects with schizophrenia. Molecular Psychiatry, 14, 1017–1023.PubMedCrossRefGoogle Scholar
  147. Schwab, S. G., Knapp, M., Mondabon, S., Hallmayer, J., Borrmann-Hassenbach, M., Albus, M., Lerer, B., Rietschel, M., Trixler, M., Maier, W., et al. (2003). Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. American Journal of Human Genetics, 72, 185–190.PubMedCrossRefGoogle Scholar
  148. Selemon, L. D., & Goldman-Rakic, P. S. (1999). The reduced neuropil hypothesis: A circuit based model of schizophrenia. Biological Psychiatry, 45, 17–25.PubMedCrossRefGoogle Scholar
  149. Sesack, S. R., Hawrylak, V. A., Matus, C., Guido, M. A., & Levey, A. I. (1998). Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. Journal of Neuroscience, 18, 2697–2708.PubMedGoogle Scholar
  150. Sherman, A. D., Davidson, A. T., Baruah, S., Hegwood, T. S., & Waziri, R. (1991a). Evidence of glutamatergic deficiency in schizophrenia. Neuroscience Letters, 121, 77–80.PubMedCrossRefGoogle Scholar
  151. Sherman, A. D., Hegwood, T. S., Baruah, S., & Waziri, R. (1991b). Deficient NMDA-mediated glutamate release from synaptosomes of schizophrenics. Biological Psychiatry, 30, 1191–1198.PubMedCrossRefGoogle Scholar
  152. Shinoe, T., Matsui, M., Taketo, M. M., & Manabe, T. (2005). Modulation of synaptic plasticity by physiological activation of M1 muscarinic acetylcholine receptors in the mouse hippocampus. Journal of Neuroscience, 25, 11194–11200.PubMedCrossRefGoogle Scholar
  153. Sigurdsson, T., Stark, K. L., Karayiorgou, M., Gogos, J. A., & Gordon, J. A. (2010). Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature, 464, 763–767.PubMedCrossRefGoogle Scholar
  154. Silberberg, G., Darvasi, A., Pinkas-Kramarski, R., & Navon, R. (2006). The involvement of ErbB4 with schizophrenia: Association and expression studies. American Journal of Medical Genetics B: Neuropsychiatric Genetics, 141B, 142–148.CrossRefGoogle Scholar
  155. Simpson, M. D., Slater, P., Deakin, J. F., Royston, M. C., & Skan, W. J. (1989). Reduced GABA uptake sites in the temporal lobe in schizophrenia. Neuroscience Letters, 107, 211–215.PubMedCrossRefGoogle Scholar
  156. Sohal, V. S., Zhang, F., Yizhar, O., & Deisseroth, K. (2009). Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature, 459, 698–702.PubMedCrossRefGoogle Scholar
  157. Song, W., Li, W., Feng, J., Heston, L. L., Scaringe, W. A., & Sommer, S. S. (2008). Identification of high risk DISC1 structural variants with a 2% attributable risk for schizophrenia. Biochemical and Biophysical Research Communications, 367, 700–706.PubMedCrossRefGoogle Scholar
  158. St Clair, D., Blackwood, D., Muir, W., Carothers, A., Walker, M., Spowart, G., Gosden, C., & Evans, H. J. (1990). Association within a family of a balanced autosomal translocation with major mental illness. Lancet, 336, 13–16.PubMedCrossRefGoogle Scholar
  159. Stefansson, H., Sarginson, J., Kong, A., Yates, P., Steinthorsdottir, V., Gudfinnsson, E., Gunnarsdottir, S., Walker, N., Petursson, H., Crombie, C., et al. (2003). Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. American Journal of Human Genetics, 72, 83–87.PubMedCrossRefGoogle Scholar
  160. Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., Chou, T. T., et al. (2002). Neuregulin 1 and susceptibility to schizophrenia. American Journal of Human Genetics, 71, 877–892.PubMedCrossRefGoogle Scholar
  161. Steiner, H., Blum, M., Kitai, S. T., & Fedi, P. (1999). Differential expression of ErbB3 and ErbB4 neuregulin receptors in dopamine neurons and forebrain areas of the adult rat. Experimental Neurology, 159, 494–503.PubMedCrossRefGoogle Scholar
  162. Stephan, K. E., Baldeweg, T., & Friston, K. J. (2006). Synaptic plasticity and dysconnection in schizophrenia. Biological Psychiatry, 59, 929–939.PubMedCrossRefGoogle Scholar
  163. Straub, R. E., MacLean, C. J., Ma, Y., Webb, B. T., Myakishev, M. V., Harris-Kerr, C., Wormley, B., Sadek, H., Kadambi, B., O’Neill, F. A., et al. (2002). Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes. Molecular Psychiatry, 7, 542–559.PubMedCrossRefGoogle Scholar
  164. Straub, R. E., MacLean, C. J., O’Neill, F. A., Burke, J., Murphy, B., Duke, F., Shinkwin, R., Webb, B. T., Zhang, J., Walsh, D., et al. (1995). A potential vulnerability locus for schizophrenia on chromosome 6p24-22: Evidence for genetic heterogeneity. Nature Genetics, 11, 287–293.PubMedCrossRefGoogle Scholar
  165. Sturgeon, R. D., Fessler, R. G., & Meltzer, H. Y. (1979). Behavioral rating scales for assessing phencyclidine-induced locomotor activity, stereotyped behavior and ataxia in rats. European Journal of Pharmacology, 59, 169–179.PubMedCrossRefGoogle Scholar
  166. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–872.PubMedCrossRefGoogle Scholar
  167. Talbot, K., Eidem, W. L., Tinsley, C. L., Benson, M. A., Thompson, E. W., Smith, R. J., Hahn, C. G., Siegel, S. J., Trojanowski, J. Q., Gur, R. E., et al. (2004). Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. The Journal of Clinical Investigation, 113, 1353–1363.PubMedGoogle Scholar
  168. Tandon, R., Dutchak, D., & Greden, J. F. (1989). Cholinergic syndrome following anticholinergic withdrawal in a schizophrenic patient abusing marijuana. The British Journal of Psychiatry, 154, 712–714.PubMedCrossRefGoogle Scholar
  169. Tang, J., LeGros, R. P., Louneva, N., Yeh, L., Cohen, J. W., Hahn, C. G., Blake, D. J., Arnold, S. E., & Talbot, K. (2009). Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Human Molecular Genetics, 18, 3851–3863.PubMedCrossRefGoogle Scholar
  170. Tang, J. X., Zhou, J., Fan, J. B., Li, X. W., Shi, Y. Y., Gu, N. F., Feng, G. Y., Xing, Y. L., Shi, J. G., & He, L. (2003). Family-based association study of DTNBP1 in 6p22.3 and schizophrenia. Molecular Psychiatry, 8, 717–718.PubMedCrossRefGoogle Scholar
  171. Thomsen, M. S., Hansen, H. H., Timmerman, D. B., & Mikkelsen, J. D. (2010). Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: From animal models to human pathophysiology. Current Pharmaceutical Design, 16, 323–343.PubMedCrossRefGoogle Scholar
  172. Thuret, S., Alavian, K. N., Gassmann, M., Lloyd, C. K., Smits, S. M., Smidt, M. P., Klein, R., Dyck, R. H., & Simon, H. H. (2004). The neuregulin receptor, ErbB4, is not required for normal development and adult maintenance of the substantia nigra pars compacta. Journal of Neurochemistry, 91, 1302–1311.PubMedCrossRefGoogle Scholar
  173. Ting, A. K., Chen, Y., Wen, L., Yin, D. M., Shen, C., Tao, Y., Liu, X., Xiong, W. C., & Mei, L. (2011). Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. Journal of Neuroscience, 31, 15–25.PubMedCrossRefGoogle Scholar
  174. Toda, M., & Abi-Dargham, A. (2007). Dopamine hypothesis of schizophrenia: Making sense of it all. Current Psychiatry Reports, 9, 329–336.PubMedCrossRefGoogle Scholar
  175. Tregellas, J. R., Tanabe, J., Rojas, D. C., Shatti, S., Olincy, A., Johnson, L., Martin, L. F., Soti, F., Kem, W. R., Leonard, S., et al. (2011). Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia. Biological Psychiatry, 69, 7–11.PubMedCrossRefGoogle Scholar
  176. Tsai, G., Passani, L. A., Slusher, B. S., Carter, R., Baer, L., Kleinman, J. E., & Coyle, J. T. (1995). Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Archives of General Psychiatry, 52, 829–836.PubMedCrossRefGoogle Scholar
  177. Tseng, K. Y., & O’Donnell, P. (2004). Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. Journal of Neuroscience, 24, 5131–5139.PubMedCrossRefGoogle Scholar
  178. Usdin, T. B., & Fischbach, G. D. (1986). Purification and characterization of a polypeptide from chick brain that promotes the accumulation of acetylcholine receptors in chick myotubes. The Journal of Cell Biology, 103, 493–507.PubMedCrossRefGoogle Scholar
  179. Usiello, A., Baik, J. H., Rouge-Pont, F., Picetti, R., Dierich, A., LeMeur, M., Piazza, P. V., & Borrelli, E. (2000). Distinct functions of the two isoforms of dopamine D2 receptors. Nature, 408, 199–203.PubMedCrossRefGoogle Scholar
  180. van Rossum, J. M. (1966). The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Archives Internationales de Pharmacodynamie et de Thérapie, 160, 492–494.PubMedGoogle Scholar
  181. Volk, D. W., Austin, M. C., Pierri, J. N., Sampson, A. R., & Lewis, D. A. (2000). Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Archives of General Psychiatry, 57, 237–245.PubMedCrossRefGoogle Scholar
  182. Volk, D., Austin, M., Pierri, J., Sampson, A., & Lewis, D. (2001). GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: Decreased expression in a subset of neurons. The American Journal of Psychiatry, 158, 256–265.PubMedCrossRefGoogle Scholar
  183. Volk, D. W., Pierri, J. N., Fritschy, J. M., Auh, S., Sampson, A. R., & Lewis, D. A. (2002). Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cerebral Cortex, 12, 1063–1070.PubMedCrossRefGoogle Scholar
  184. Vullhorst, D., Neddens, J., Karavanova, I., Tricoire, L., Petralia, R. S., McBain, C. J., & Buonanno, A. (2009). Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. Journal of Neuroscience, 29, 12255–12264.PubMedCrossRefGoogle Scholar
  185. Weickert, C. S., Rothmond, D. A., Hyde, T. M., Kleinman, J. E., & Straub, R. E. (2008). Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophrenia Research, 98, 105–110.PubMedCrossRefGoogle Scholar
  186. Weickert, C. S., Straub, R. E., McClintock, B. W., Matsumoto, M., Hashimoto, R., Hyde, T. M., Herman, M. M., Weinberger, D. R., & Kleinman, J. E. (2004). Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Archives of General Psychiatry, 61, 544–555.PubMedCrossRefGoogle Scholar
  187. Wen, L., Lu, Y. S., Zhu, X. H., Li, X. M., Woo, R. S., Chen, Y. J., Yin, D. M., Lai, C., Terry, A. V., Jr., Vazdarjanova, A., et al. (2010). Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proceedings of the National Academy of Sciences of the United States of America, 107, 1211–1216.PubMedCrossRefGoogle Scholar
  188. Whittington, M. A., Cunningham, M. O., LeBeau, F. E., Racca, C., & Traub, R. D. (2011). Multiple origins of the cortical gamma rhythm. Developmental Neurobiology, 71, 92–106.PubMedCrossRefGoogle Scholar
  189. Williams, G. V., & Goldman-Rakic, P. S. (1995). Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature, 376, 572–575.PubMedCrossRefGoogle Scholar
  190. Wong, D. F., Wagner, H. N., Jr., Tune, L. E., Dannals, R. F., Pearlson, G. D., Links, J. M., Tamminga, C. A., Broussolle, E. P., Ravert, H. T., Wilson, A. A., et al. (1986). Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science, 234, 1558–1563.PubMedCrossRefGoogle Scholar
  191. Woo, R. S., Li, X. M., Tao, Y., Carpenter-Hyland, E., Huang, Y. Z., Weber, J., Neiswender, H., Dong, X. P., Wu, J., Gassmann, M., et al. (2007). Neuregulin-1 enhances depolarization-induced GABA release. Neuron, 54, 599–610.PubMedCrossRefGoogle Scholar
  192. Woo, T. U., Miller, J. L., & Lewis, D. A. (1997). Schizophrenia and the parvalbumin-containing class of cortical local circuit neurons. The American Journal of Psychiatry, 154, 1013–1015.PubMedGoogle Scholar
  193. Woo, T. U., Whitehead, R. E., Melchitzky, D. S., & Lewis, D. A. (1998). A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 95, 5341–5346.PubMedCrossRefGoogle Scholar
  194. Yang, X., Kuo, Y., Devay, P., Yu, C., & Role, L. (1998). A cysteine-rich isoform of neuregulin controls the level of expression of neuronal nicotinic receptor channels during synaptogenesis. Neuron, 20, 255–270.PubMedCrossRefGoogle Scholar
  195. Yang, J. Z., Si, T. M., Ruan, Y., Ling, Y. S., Han, Y. H., Wang, X. L., Zhou, M., Zhang, H. Y., Kong, Q. M., Liu, C., et al. (2003). Association study of neuregulin 1 gene with schizophrenia. Molecular Psychiatry, 8, 706–709.PubMedCrossRefGoogle Scholar
  196. Yau, H. J., Wang, H. F., Lai, C., & Liu, F. C. (2003). Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: Preferential expression by interneurons tangentially migrating from the ganglionic eminences. Cerebral Cortex, 13, 252–264.PubMedCrossRefGoogle Scholar
  197. Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318, 1917–1920.PubMedCrossRefGoogle Scholar
  198. Yurek, D. M., Zhang, L., Fletcher-Turner, A., & Seroogy, K. B. (2004). Supranigral injection of neuregulin1-beta induces striatal dopamine overflow. Brain Research, 1028, 116–119.PubMedCrossRefGoogle Scholar
  199. Zavitsanou, K., Katsifis, A., Mattner, F., & Huang, X. F. (2004). Investigation of m1/m4 muscarinic receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression disorder. Neuropsychopharmacol, 29, 619–625.CrossRefGoogle Scholar
  200. Zhang, L., Fletcher-Turner, A., Marchionni, M. A., Apparsundaram, S., Lundgren, K. H., Yurek, D. M., & Seroogy, K. B. (2004). Neurotrophic and neuroprotective effects of the neuregulin glial growth factor-2 on dopaminergic neurons in rat primary midbrain cultures. Journal of Neurochemistry, 91, 1358–1368.PubMedCrossRefGoogle Scholar
  201. Zhang, Y., Hamilton, S. E., Nathanson, N. M., & Yan, J. (2006). Decreased input-specific plasticity of the auditory cortex in mice lacking M1 muscarinic acetylcholine receptors. Cerebral Cortex, 16, 1258–1265.PubMedCrossRefGoogle Scholar
  202. Zheng, Y., Watakabe, A., Takada, M., Kakita, A., Namba, H., Takahashi, H., Yamamori, T., & Nawa, H. (2009). Expression of ErbB4 in substantia nigra dopamine neurons of monkeys and humans. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33, 701–706.CrossRefGoogle Scholar
  203. Zhong, C., Du, C., Hancock, M., Mertz, M., Talmage, D. A., & Role, L. W. (2008). Presynaptic type III neuregulin 1 is required for sustained enhancement of hippocampal transmission by nicotine and for axonal targeting of alpha7 nicotinic acetylcholine receptors. Journal of Neuroscience, 28, 9111–9116.PubMedCrossRefGoogle Scholar
  204. Zvara, A., Szekeres, G., Janka, Z., Kelemen, J. Z., Cimmer, C., Santha, M., & Puskas, L. G. (2005). Over-expression of dopamine D2 receptor and inwardly rectifying potassium channel genes in drug-naive schizophrenic peripheral blood lymphocytes as potential diagnostic markers. Disease Markers, 21, 61–69.PubMedGoogle Scholar

Copyright information

© Springer-Verlag/WIen 2012

Authors and Affiliations

  • Dong-Min Yin
    • 1
  • Yong-Jun Chen
    • 1
  • Anupama Sathyamurthy
    • 1
  • Wen-Cheng Xiong
    • 1
  • Lin Mei
    • 1
    Email author
  1. 1.Department of Neurology, Institute of Molecular Medicine and GeneticsGeorgia Health Sciences UniversityAugustaUSA

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