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Translational and developmental perspective on N-methyl-D-aspartate synaptic deficits in schizophrenia

Published online by Cambridge University Press:  09 August 2006

ANGUS W. MacDONALD III
Affiliation:
University of Minnesota
MATTHEW V. CHAFEE
Affiliation:
University of Minnesota School of Medicine, and Brain Sciences Center, Minneapolis Veterans Administration Medical Center

Abstract

Schizophrenia has long been approached from a translational perspective; however, new findings from the past decade have radically affected the dominant accounts of this illness. It is now possible to derive a consistent account of one contributing cause of schizophrenia across multiple levels of analysis, from genes to receptors, functional neuroanatomy, cognition, and symptoms. To this end, we summarize the data attributing the disorganization symptoms of schizophrenia to a failure of executive, prefrontal cortical processes. We describe the hypothesis that this failure reflects an impairment in N-methyl-D-aspartate (NMDA) glutamatergic neurotransmission, that is likely to involve both the dysregulated function of NMDA synapses, as well as the physical loss of NMDA synapses, particularly in prefrontal cortex. Dysregulation in NMDA synaptic function can be in turn attributed to polymorphisms in a variety of genes (regulator of G-protein signaling 4, dystrobrevin binding protein 1, neuregulin-1, d-amino acid oxidase activator, and others) that have been linked to schizophrenia and are likely to impact NMDA-mediated synaptic neuroplasticity. Although the science of schizophrenia is not yet at a point where any domain or set of findings provides strong constraints across other levels of analysis, the further development of evidence for this chain of causation can provide increasingly strong tests of the NMDA synapse deficit theory.This work was supported by Grant MH069675 from the National Institute of Health. The authors thank Scott Sponheim and Irving Gottesman for their perspectives and insights on various aspects of the manuscript.

Type
Research Article
Copyright
© 2006 Cambridge University Press

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References

REFERENCES

Adler, C. M., Goldberg, T. E., Malhotra, A. K., Pickar, D., & Breier, A. (1998). Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers. Biological Psychiatry, 43, 811816.Google Scholar
Andreasen, N. C., Rezai, K., Alliger, R., Swayze, V., Flaum, M., Kirchner, P., et al. (1992). Hypofrontality in neuroleptic naive patients and in patients with chronic schizophrenia: Assessment with xenon 133 single photon emission computed tomography and the tower of london. Archives of General Psychiatry, 49, 943958.Google Scholar
Arndt, S., Alliger, R. J., & Andreasen, N. C. (1991). The distinction of positive and negative symptoms: The failure of the two dimensional model. British Journal of Psychiatry, 158, 4650.Google Scholar
Baddeley, A. D., & Hitch, G. J. (1974). Working memory. In G. Bower (Ed.), The psychology of learning and motivation (Vol. 8, pp. 4790). San Diego, CA: Academic Press.
Barch, D., Carter, C., MacDonald, A., Braver, T., & Cohen, J. (2003). Context processing deficits in schizophrenia: Diagnostic specificity, four-week course, and relationships to clinical symptoms. Journal of Abnormal Psychology, 112, 132143.Google Scholar
Barch, D. M., Braver, T. S., Nystrom, L. E., Forman, S. D., Noll, D. C., & Cohen, J. D. (1997). Dissociating working memory from task difficulty in human prefrontal cortex. Neuropsychologia, 35, 13731380.Google Scholar
Barch, D. M., Carter, C. S., Braver, T. S., Sabb, F. W., MacDonald, A., III, Noll, D. C., et al. (2001). Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Archives of General Psychiatry, 58, 280288.Google Scholar
Becker, T. M., Snitz, B. E., Kerns, J. G., Barch, D. M., Yablonsky, E. J., Holmes, A., et al. (2003). Context processing deficits and associated hypofrontality predict functional outcome in first episode schizophrenia patients. Paper presented at the Society for Neuroscience.
Benes, F. M., & Berretta, S. (2001). GABAergic interneurons: Implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology, 25, 127.Google Scholar
Bliss, T. V., & Lomo, T. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. Journal of Physiology, 232, 331356.Google Scholar
Bourgeois, J. P., Goldman-Rakic, P. S., & Rakic, P. (1994). Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cerebral Cortex, 4, 7896.Google Scholar
Cardno, A. G., Sham, P. C., Murray, R. M., & McGuffin, P. (2001). Twin study of symptom dimensions in psychosis. British Journal of Psychiatry, 179, 3945.Google Scholar
Carter, C. S., Braver, T. S., Barch, D. M., Botvinick, M., Noll, D., & Cohen, J. D. (1998). Anterior cingulate cortex, error detection, and the on line monitoring of performance. Science, 280, 747749.Google Scholar
Chapman, L. J., & Chapman, J. P. (1973). Problems in the measurement of cognitive deficit. Psychological Bulletin, 79, 380385.Google Scholar
Chowdari, K. V., Mirnics, K., Semwal, P., Wood, J., Lawrence, E., Bhatia, T., et al. (2002). Association and linkage analyses of rgs4 polymorphisms in schizophrenia. Human Molecular Genetics, 11, 13731380.Google Scholar
Chumakov, I., Blumenfeld, M., Guerassimenko, O., Cavarec, L., Palicio, M., Abderrahim, H., et al. (2002). Genetic and physiological data implicating the new human gene g72 and the gene for d-amino acid oxidase in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 99, 1367513680.Google Scholar
Cicchetti, D., & Blender, J. A. (2004). A multiple-levels-of-analysis approach to the study of developmental processes in maltreated children. Proceedings of the National Academy of Science of the United States of America, 101, 1731617321.Google Scholar
Cicchetti, D., & Blender, J. A. (in press). A multiple-levels-of-analysis perspective on resilience: Implications for the developing brain, neuroplasticity and preventative interventions. Annals of the New York Academy of Sciences.
Cicchetti, D., & Cannon, T. D. (1999). Neurodevelopmental processes in the ontogenesis and epigenesis of psychopathology. Developmental Psychopathology, 11, 375393.Google Scholar
Cicchetti, D., & Rogosch, F. A. (2002). A developmental psychopathology perspective on adolescence. Journal of Consulting and Clinical Psychology, 70, 620.Google Scholar
Cohen, J. D., Barch, D. M., Carter, C. S., & Servan-Schreiber, D. (1999). Context-processing deficits in schizophrenia: Converging evidence from three theoretically motivated cognitive tasks. Journal of Abnormal Psychology, 108, 120133.Google Scholar
Cohen, J. D., & Servan-Schreiber, D. (1992). Context, cortex and dopamine: A connectionist approach to behavior and biology in schizophrenia. Psychological Review, 99, 4577.Google Scholar
Coyle, J. T., & Tsai, G. (2004). The NMDA receptor glycine modulatory site: A therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology (Berlin), 174, 3238.Google Scholar
Crow, T. J. (1980). Molecular pathology of schizophrenia: More than one dimension of pathology? British Medical Journal, 280, 6668.Google Scholar
Davison, L. A. (1974). Current status of clinical neuropsychology. In R. M. Reitan & L. A. Davison (Eds.), Clinical neuropsychology: Current status and applications (pp. 211236). Washington, DC: Wiley.
Devlin, B., Bacanu, S. A., Roeder, K., Reimherr, F., Wender, P., Galke, B., et al. (2002). Genome-wide multipoint linkage analyses of multiplex schizophrenia pedigrees from the oceanic nation of palau. Molecular Psychiatry, 7, 689694.Google Scholar
Domino, E. F., & Luby, E. D. (1981). Abnormal mental states induced by phencyclidine as a model of schizophrenia. In E. F. Domino (Ed.), PCP (phencyclidine): Historical and current perspectives (pp. 401418). Ann Arbor, MI: NPP Books.
Ebmeier, K. P., Lawrie, S. M., Blackwood, D. H. R., Johnstone, E. C., & Goodwin, G. M. (1995). Hypofrontality revisited: A high resolution single photon emission computer tomography study in schizophrenia. Journal of Neurology, Neurosurgery and Psychiatry, 58, 452456.Google Scholar
Egan, M., Straub, R., Goldberg, T., Yakub, I., Callicott, J., Hariri, A., et al. (2004). Variation in grm3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 101, 1260412609.Google Scholar
Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti, C. M., Straub, R. E., et al. (2001). Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proceedings of the National Academy of Science of the United States of America, 98, 69176922.Google Scholar
Fan, J.-B., Zhang, C.-S., Gu, N.-F., Li, X.-W., Sun, W.-W., Wang, H.-Y., et al. (2005). Catechol-o-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: A large-scale association study plus meta-analysis. Biological Psychiatry, 57, 139144.Google Scholar
Friston, K. J., & Frith, C. D. (1995). Schizophrenia: A disconnection syndrome? Clinical Neuroscience, 3, 8997.Google Scholar
Fujii, Y., Shibata, H., Kikuta, R., Makino, C., Tani, A., Hirata, N., et al. (2003). Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (grm3) with schizophrenia. Psychiatric Genetics, 13, 7176.Google Scholar
Gerber, D., Hall, D., Miyakawa, T., Demars, S., Gogos, J., Karayiorgou, M., et al. (2003). Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, ppp3cc, encoding the calcineurin gamma subunit. Proceedings of the National Academy of Sciences of the United States of America, 100, 89938998.Google Scholar
Glahn, D. C., Ragland, J. D., Adramoff, A., Barrett, J., Laird, A. R., Bearden, C. E., et al. (2005). Beyond hypofrontality: A quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Human Brain Mapping, 25, 6069.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, 6573.Google Scholar
Gottesman, I. I. (1991). Schizophrenia genesis: The origins of madness. New York: W.H. Freeman.
Gottesman, I. I., & Shields, J. (1966). Schizophrenia in twins: 16 years' consecutive admissions to a psychiatric clinic. British Journal of Psychiatry, 112, 809818.Google Scholar
Gur, R. C., & Gur, R. E. (1995). Hypofrontality in schizophrenia: Rip. Lancet, 345, 13381340.Google Scholar
Hebb, D. O. (1949). The organization of behaviour. New York: Wiley.
Heinrichs, R. W. (2005). The primacy of cognition in schizophrenia. American Psychologist, 60, 229242.Google Scholar
Herron, C. E., Lester, R. A., Coan, E. J., & Collingridge, G. L. (1986). Frequency-dependent involvement of nmda receptors in the hippocampus: A novel synaptic mechanism. Nature, 322, 265268.Google Scholar
Hill, K., Mann, L., Laws, K. R., Stephenson, C. M. E., Nimmo-Smith, I., & McKenna, P.J. (2004). Hypofrontality in schizophrenia: A meta-analysis of functional imaging studies. Acta Psychiatricia Scandinavica, 110, 243256.Google Scholar
Hoffman, R. E., & McGlashan, T. H. (1993). Parallel distributed processing and the emergence of schizophrenic symptoms. Schizophrenia Bulletin, 19, 119140.Google Scholar
Hoffman, R. E., & McGlashan, T. H. (1997). Synaptic elimination, neurodevelopment, and the mechanism of hallucinated “voices” in schizophrenia. American Journal of Psychiatry, 154, 16831689.Google Scholar
Hoffman, R. E., & McGlashan, T. H. (2001). Neural network models of schizophrenia. Neuroscientist, 7, 441454.Google Scholar
Holmes, A. J., MacDonald, A. W., III, Carter, C. S., Barch, D. M., Stenger, V. A., & Cohen, J. D. (2005). Prefrontal functioning during context processing in schizophrenia and major depression: An event-related fMRI study. Schizophrenia Research, 76, 199206.Google Scholar
Huttenlocher, P. R. (1979). Synaptic density in human frontal cortex—Developmental changes and effects of aging. Brain Research, 163, 195205.Google Scholar
Huttenlocher, P. R., & Dabholkar, A. S. (1997). Regional differences in synaptogenesis in human cerebral cortex. Journal of Comparative Neurology, 387, 167178.Google Scholar
Ingvar, D. H., & Franzen, G. (1974). Distribution of cerebral activity in chronic schizophrenia. Lancet, 2, 14841486.Google Scholar
Javitt, D. C., Jotkowitz, A., Sircar, R., & Zukin, S. R. (1987). Non-competitive regulation of phencyclidine/sigma-receptors by the N-methyl-D-aspartate receptor antagonist d-(−)-2-amino-5-phosphonovaleric acid. Neuroscience Letters, 78, 193198.Google Scholar
Javitt, D. C., & Zukin, S. R. (1991). Recent advances in the phencyclidine model of schizophrenia. American Journal of Psychiatry, 148, 13011308.Google Scholar
Jentsch, J. D., Redmond, D. E., Jr., Elsworth, J. D., Taylor, J. R., Youngren, K. D., & Roth, R. H. (1997). Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science, 277, 953955.Google Scholar
Jernigan, T. L., Sargent, T., III, Pfefferbaum, A., Kusubov, N., & Stahl, S. M. (1985). 18Fluorodeoxyglucose PET in schizophrenia. Psychiatry Research, 16, 317329.Google Scholar
Joyce, E., & Huddy, V. (2004). Defining the cognitive impairment in schizophrenia. Psychological Medicine, 34, 11511155.Google Scholar
Kety, S. S., Rosenthal, W., Wender, P. H., & Schulsinger, F. (1971). Mental illness in the biological and adoptive families of adopted schizophrenics. American Journal of Psychiatry, 128, 302306.Google Scholar
Kippin, T. E., Kapur, S., & van der Kooy, D. (2005). Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. Journal of Neuroscience, 25, 58155823.Google Scholar
Knight, R. (1984). Converging models of cognitive deficits in schizophrenia. In W. Spaulding & J. Coles (Eds.), Nebraska Symposium on Motivation: Theories of schizophrenia and psychosis (Vol. 31, pp. 93156). Lincoln, NE: University of Nebraska Press.
Korostishevsky, M., Kaganovich, M., Cholostoy, A., Ashkenazi, M., Ratner, Y., Dahary, D., et al. (2004). Is the g72/g30 locus associated with schizophrenia? Single nucleotide polymorphisms, haplotypes, and gene expression analysis. Biological Psychiatry, 56, 169176.Google Scholar
Krystal, J. H., Karper, L. P., Seibyl, J. P., Freeman, G. K., Delaney, R., Bremner, J. D., et al. (1994). Subanesthetic effects of the noncompetitive nmda antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of General Psychiatry, 51, 199214.Google Scholar
Laruelle, M., Kegeles, L. S., & Abi-Dargham, A. (2003). Glutamate, dopamine and schizophrenia: From pathophysiology to treatment. Annals of the New York Academy of Sciences, 1003, 138158.Google Scholar
Lewis, D. A. (1997). Development of the prefrontal cortex during adolescence: Insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology, 16, 385398.Google Scholar
Lewis, D. A., Glantz, L. A., Pierri, J. N., & Sweet, R. A. (2003). Altered cortical glutamate neurotransmission in schizophrenia: Evidence from morphological studies of pyramidal neurons. Annals of the New York Academy of Sciences, 1003, 102112.Google Scholar
Lewis, D. A., & Gonzalez-Burgos, G. (2000). Intrinsic excitatory connections in the prefrontal cortex and the pathophysiology of schizophrenia. Brain Research Bulletin, 52, 309317.Google Scholar
Liddle, P. F. (1987). Syndromes of chronic schizophrenia: A re-examination of the positive-negative dichotomy. British Journal of Psychiatry, 151, 145151.Google Scholar
Liu, H., Heath, S. C., Sobin, C., Roos, J. L., Galke, B. L., Blundell, M. L., et al. (2002). Genetic variation at the 22q11 prodh2/dgcr6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proceedings of the National Academy of Science of the United States of America, 99, 37173722.Google Scholar
Loftus, J., DeLisi, L., & Crow, T. (1998). Familial associations of subsyndromes of psychosis in affected sibling pairs with schizophrenia and schizoaffective disorder. Psychiatry Research, 80, 101111.Google Scholar
Logothetis, N. K. (2002). The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal. Philosophical Transactions of the Royal Society of London, Series B, Biological Sciences, 357, 10031037.Google Scholar
Luisada, P. V. (1978). The phencyclidine psychosis: Phenomenology and treatment. NIDA Research Monograph, 1, 241253.Google Scholar
MacDonald, A. W., III, Becker, T. M., & Carter, C. S. (in press). Functional MRI study of cognitive control in the healthy relatives of schizophrenia patients. Biological Psychiatry.
MacDonald, A. W., III, & Carter, C. S. (2002). Cognitive experimental approaches to investigating impaired cognition in schizophrenia: A paradigm shift. Journal of Clinical and Experimental Neuropsychology, 24, 873882.Google Scholar
MacDonald, A. W., III, & Carter, C. S. (2003). Event-related fMRI study of context processing in dorsolateral prefrontal cortex of patients with schizophrenia. Journal of Abnormal Psychology, 112, 689697.Google Scholar
MacDonald, A. W., III, Carter, C. S., Kerns, J. G., Ursu, S., Barch, D. M., Holmes, A., et al. (2005). Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in a never-medicated first-episode sample. American Journal of Psychiatry, 162, 475484.Google Scholar
MacDonald, A. W., III, Goghari, V. M., Hicks, B. M., Flory, J. D., Carter, C. S., & Manuck, S. B. (2005). A convergent-divergent approach to context processing, general intellectual functioning and the genetic liability to schizophrenia. Neuropsychology, 19, 814821.Google Scholar
MacDonald, A. W., III, & Kang, S. S. (in press). Cassandra's calculations: Simulation studies of the psychometric confound. In F. Columbus (Ed.), Schizophrenia psychology: New research. Hauppauge, NY: Nove Science Publishers.
MacDonald, A. W., III, Pogue-Geile, M. F., Johnson, M. K., & Carter, C. S. (2003). A specific deficit in context processing in the unaffected siblings of patients with schizophrenia. Archives of General Psychiatry, 60, 5765.Google Scholar
Malinow, R., & Miller, J. P. (1986). Postsynaptic hyperpolarization during conditioning reversibly blocks induction of long-term potentiation. Nature, 320, 529530.Google Scholar
Mayer, M. L., Westbrook, G. L., & Guthrie, P. B. (1984). Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature, 309, 261263.Google Scholar
Meehl, P. E. (1962). Schizotaxia, schizotypy, schizophrenia. American Psychologist, 17, 827838.Google Scholar
Millar, J. K., Wilson-Annan, J. C., Anderson, S., Christie, S., Taylor, M. S., Semple, C. A., et al. (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Human Molecular Genetics, 22, 14151423.Google Scholar
Miller, E. K. (2000). The prefrontal cortex and cognitive control. Nature Reviews, 1, 5965.Google Scholar
Mirnics, K., Middleton, F. A., Stanwood, G. D., Lewis, D. A., & Levitt, P. (2001). Disease-specific changes in regular of g-protein signaling 4 (rgs4) expression in schizophrenia. Molecular Psychiatry, 6, 293301.Google Scholar
Moghaddam, B. (2003). Bringing order to the glutamate chaos in schizophrenia. Neuron, 40, 881884.Google Scholar
Moises, H. W., Zoega, T., & Gottesman, I. I. (2002). The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry, 2, 8.Google Scholar
Numakawa, T., Yagasaki, Y., Ishimoto, T., Okada, T., Suzuki, T., Iwata, N., et al. (2004). Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Human Molecular Genetics, 13, 26992708.Google Scholar
O'Donnell, P., Lewis, B. L., Weinberger, D. R., & Lipska, B. K. (2002). Neonatal hippocampal damage alters electrophysiological properties of prefrontal cortical neurons in adult rats. Cerebral Cortex, 12, 975982.Google Scholar
Ogawa, S., Lee, T. M., Kay, A. R., & Tank, D. W. (1990). Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proceedings of the National Academy of Sciences of the United States of America, 87, 98689872.Google Scholar
Owen, M. J., Williams, N. M., & O'Donovan, M. C. (2004). The molecular genetics of schizophrenia: New findings promise new insights. Molecular Psychiatry, 9, 1427.Google Scholar
Peralta, V., & Cuesta, M. (1999). Dimensional structure of psychotic symptoms: An item-level analysis of saps and sans symptoms in psychotic disorders. Schizophrenia Research, 38, 1326.Google Scholar
Perlstein, W. M., Dixit, N. K., Carter, C. S., Noll, D. C., & Cohen, J. D. (2003). Prefrontal cortex dysfunction mediates deficits in working memory and prepotent responding in schizophrenia. Biological Psychiatry, 53, 2538.Google Scholar
Phillips, W. A., & Silverstein, S. M. (2003). Convergence of biological and psychological perspectives on cognitive coordination in schizophrenia. Behavioral and Brain Sciences, 26, 65138.Google Scholar
Pierri, J. N., Chaudry, A. S., Woo, T. U., & Lewis, D. A. (1999). Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. American Journal Psychiatry, 156, 17091719.Google Scholar
Plum, F. (1972). Prospects for research on schizophrenia. 3. Neuropsychology. Neuropathological findings. Neurosciences Research Program Bulletin, 10, 384388.Google Scholar
Rakic, P., Bourgeois, J. P., Eckenhoff, M. F., Zecevic, N., & Goldman-Rakic, P. S. (1986). Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science, 232, 232235.Google Scholar
Rice, S., Niu, N., Berman, D., Heston, L., & Sobell, J. (2001). Identification of single nucleotide polymorphisms (snps) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the nmdar1 receptor gene in schizophrenic patients. Molecular Psychiatry, 6, 274284.Google Scholar
Rosvold, K. E., Mirsky, A. F., Sarason, I., Bransome, E. D., & Beck, L. H. (1956). A continuous performance test of brain damage. Journal of Consulting Psychology, 20, 343350.Google Scholar
Rudin, E. (Ed.). (1916). Studien über vererbung und entstehung geistiger störungen. I. Zur vererbung und neuentstehung der dementia praecox. [Studies on the inheritance and origin of mental illness. I. The problem of the inheritance and primary origin of Dementia praecox] (Vol. 12). Berlin: Springer.
Selemon, L. D., & Goldman-Rakic, P. S. (1999). The reduced neuropil hypothesis: A circuit based model of schizophrenia. Biological Psychiatry, 45, 1725.Google Scholar
Selemon, L. D., Kleinman, J. E., Herman, M. M., & Goldman-Rakic, P. S. (2002). Smaller frontal gray matter volume in postmortem schizophrenic brains. American Journal of Psychiatry, 159, 19831991.Google Scholar
Selemon, L. D., Rajkowska, G., & Goldman-Rakic, P. S. (1995). Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Archives of General Psychiatry, 52, 805818; discussion 819–820.Google Scholar
Servan-Schreiber, D., Cohen, J., & Steingard, S. (1996). Schizophrenic deficits in the processing of context: A test of a theoretical model. Archives of General Psychiatry, 53, 11051112.Google Scholar
Shi, S. H., Hayashi, Y., Petralia, R. S., Zaman, S. H., Wenthold, R. J., Svoboda, K., et al. (1999). Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science, 284, 18111816.Google Scholar
Shifman, S., Bronstein, M., Siante-Shalom, A., Lev-Lehman, E., Weizman, A., Reznik, I., et al. (2002). A high selective association between a COMT haplotype and schizophrenia. American Journal of Human Genetics, 72, 12961302.Google Scholar
Simon, J. R. (1990). The effects of an irrelevant directional cue on human information processing. In R. W. Proctor & T. G. Reeve (Eds.), Stimulus–response compatibility: An integrated perspective (pp. 3186). Amsterdam: North-Holland.
Stefani, M. R., & Moghaddam, B. (2005). Systemic and prefrontal cortical NMDA receptor blockade differentially affect discrimination learning and set-shift ability in rats. Behavioral Neuroscience, 119, 420428.Google Scholar
Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., et al. (2002). Neuregulin 1 and susceptibility to schizophrenia. American Journal of Human Genetics, 71, 877892.Google Scholar
Stephan, K. E., Baldeweg, T., & Friston, K. J. (2006). Synaptic plasticity and dysconnection in schizophrenia. Biological Psychiatry, 59, 929939.Google Scholar
Stoet, G., & Snyder, L. H. (2005). Effects of the NMDA antagonist ketamine on task-switching performance: Evidence for specific impairments of executive control. Neuropsychopharmacology [Advance online publication, doi: 10.1038/sj.npp.1300930].Google Scholar
Straub, R. E., Jiang, Y., MacLean, C. J., Ma, Y., Webb, B. T., Myakishev, M. V., et al. (2002). Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. American Journal of Human Genetics, 71, 337348.Google Scholar
Strauss, M. E. (2001). Demonstrating specific cognitive deficits: A psychometric perspective. Journal of Abnormal Psychology, 110, 614.Google Scholar
Thune, J. J., Uylings, H. B., & Pakkenberg, B. (2001). No deficit in total number of neurons in the prefrontal cortex in schizophrenics. Journal of Psychiatric Research, 35, 1521.Google Scholar
Toyooka, K., Muratake, T., Tanaka, T., Igarashi, S., Watanabe, H., Takeuchi, H., et al. (1999). 14-3-3 protein eta chain gene (YWHAH) polymorphism and its genetic association with schizophrenia. American Journal of Medical Genetics, 88, 164167.Google Scholar
Vawter, M., Crook, J., Hyde, T., Kleinman, J. E., Weinberger, D., Becker, K., et al. (2002). Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: A preliminary study. Schizophrenia Research, 58, 1120.Google Scholar
Weickert, C. S., Straub, R. E., McClintock, B. W., Matsumoto, M., Hashimoto, R., Hyde, T. M., et al. (2004). Human dysbindin (dtnbp1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Archives of General Psychiatry, 61, 544555.Google Scholar
Weinberger, D. R., Berman, K., & Zec, R. (1986). Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia I. Regional cerebral bloodflow evidence. Archives of General Psychiatry, 43, 114124.Google Scholar
Woo, T. U., Pucak, M. L., Kye, C. H., Matus, C. V., & Lewis, D. A. (1997). Peripubertal refinement of the intrinsic and associational circuitry in monkey prefrontal cortex. Neuroscience, 80, 11491158.Google Scholar