Skip to main content

Synaptic Dysfunction in Schizophrenia

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((volume 970))

Abstract

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.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Abi-Dargham, A., & Moore, H. (2003). Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. The Neuroscientist, 9, 404–416.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Angrist, B. M., & Gershon, S. (1970). The phenomenology of experimentally induced amphetamine psychosis–preliminary observations. Biological Psychiatry, 2, 95–107.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Beasley, C. L., & Reynolds, G. P. (1997). Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics. Schizophrenia Research, 24, 349–355.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Bell, D. S. (1973). The experimental reproduction of amphetamine psychosis. Archives of General Psychiatry, 29, 35–40.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Eastwood, S. L. (2004). The synaptic pathology of schizophrenia: Is aberrant neurodevelopment and plasticity to blame? International Review of Neurobiology, 59, 47–72.

    Article  PubMed  CAS  Google Scholar 

  • Fauman, B., Aldinger, G., Fauman, M., & Rosen, P. (1976). Psychiatric sequelae of phencyclidine abuse. Clinical Toxicology, 9, 529–538.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Forrer, G. R., & Miller, J. J. (1958). Atropine coma: A somatic therapy in psychiatry. The American Journal of Psychiatry, 115, 455–458.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Gerfen, C. R. (1992). The neostriatal mosaic: Multiple levels of compartmental organization. Trends in Neurosciences, 15, 133–139.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M., & Deisseroth, K. (2009). Optical deconstruction of parkinsonian neural circuitry. Science, 324, 354–359.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Iyengar, S. S., & Mott, D. D. (2008). Neuregulin blocks synaptic strengthening after epileptiform activity in the rat hippocampus. Brain Research, 1208, 67–73.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Keverne, E. B. (1999). GABA-ergic neurons and the neurobiology of schizophrenia and other psychoses. Brain Research Bulletin, 48, 467–473.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Lahti, A. C., Koffel, B., LaPorte, D., & Tamminga, C. A. (1995). Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacol, 13, 9–19.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Lai, C., & Lemke, G. (1991). An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system. Neuron, 6, 691–704.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Lieberman, J. A., Kane, J. M., & Alvir, J. (1987). Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology, 91, 415–433.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Lohr, J. B., & Flynn, K. (1992). Smoking and schizophrenia. Schizophrenia Research, 8, 93–102.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • McBain, C. J., & Kauer, J. A. (2009). Presynaptic plasticity: Targeted control of inhibitory networks. Current Opinion in Neurobiology, 19, 254–262.

    Article  PubMed  CAS  Google Scholar 

  • McCullumsmith, R. E., Clinton, S. M., & Meador-Woodruff, J. H. (2004). Schizophrenia as a disorder of neuroplasticity. International Review of Neurobiology, 59, 19–45.

    Article  PubMed  CAS  Google Scholar 

  • Mei, L., & Xiong, W. C. (2008). Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nature Reviews Neuroscience, 9, 437–452.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam, B., & Adams, B. W. (1998). Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science, 281, 1349–1352.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Neubauer, H., Adams, M., & Redfern, P. (1975). The role of central cholinergic mechanisms in schizophrenia. Medical Hypotheses, 1, 32–34.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Paterson, D., & Nordberg, A. (2000). Neuronal nicotinic receptors in the human brain. Progress in Neurobiology, 61, 75–111.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Petreanu, L., Mao, T., Sternson, S. M., & Svoboda, K. (2009). The subcellular organization of neocortical excitatory connections. Nature, 457, 1142–1145.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Sams-Dodd, F. (1996). Phencyclidine-induced stereotyped behaviour and social isolation in rats: A possible animal model of schizophrenia. Behavioural Pharmacology, 7, 3–23.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Sawaguchi, T., & Goldman-Rakic, P. S. (1991). D1 dopamine receptors in prefrontal cortex: Involvement in working memory. Science, 251, 947–950.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Selemon, L. D., & Goldman-Rakic, P. S. (1999). The reduced neuropil hypothesis: A circuit based model of schizophrenia. Biological Psychiatry, 45, 17–25.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Sohal, V. S., Zhang, F., Yizhar, O., & Deisseroth, K. (2009). Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature, 459, 698–702.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Stephan, K. E., Baldeweg, T., & Friston, K. J. (2006). Synaptic plasticity and dysconnection in schizophrenia. Biological Psychiatry, 59, 929–939.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Toda, M., & Abi-Dargham, A. (2007). Dopamine hypothesis of schizophrenia: Making sense of it all. Current Psychiatry Reports, 9, 329–336.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Williams, G. V., & Goldman-Rakic, P. S. (1995). Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature, 376, 572–575.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lin Mei .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag/WIen

About this chapter

Cite this chapter

Yin, DM., Chen, YJ., Sathyamurthy, A., Xiong, WC., Mei, L. (2012). Synaptic Dysfunction in Schizophrenia. In: Kreutz, M., Sala, C. (eds) Synaptic Plasticity. Advances in Experimental Medicine and Biology, vol 970. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0932-8_22

Download citation

Publish with us

Policies and ethics