Skip to main content

Main menu

  • Home
  • Issues
    • Issue in progress
    • Issues by date
  • Sections
    • Editorial
    • Review
    • Research
    • Commentary
    • Psychopharmacology for the Clinician
    • Letters to the Editor
  • Topic Collections
  • Instructions for Authors
    • Overview for authors
    • Submission checklist
    • Editorial policies
    • Publication fees
    • Submit a manuscript
    • Dr. Francis Wayne Quan Memorial Prize
    • Open access
  • Alerts
    • Email alerts
    • RSS
  • About
    • General information
    • Staff
    • Editorial Board
    • Contact
  • CMAJ JOURNALS
    • CMAJ
    • CMAJ Open
    • CJS
    • JAMC

User menu

Search

  • Advanced search
JPN
  • CMAJ JOURNALS
    • CMAJ
    • CMAJ Open
    • CJS
    • JAMC
JPN

Advanced Search

  • Home
  • Issues
    • Issue in progress
    • Issues by date
  • Sections
    • Editorial
    • Review
    • Research
    • Commentary
    • Psychopharmacology for the Clinician
    • Letters to the Editor
  • Topic Collections
  • Instructions for Authors
    • Overview for authors
    • Submission checklist
    • Editorial policies
    • Publication fees
    • Submit a manuscript
    • Dr. Francis Wayne Quan Memorial Prize
    • Open access
  • Alerts
    • Email alerts
    • RSS
  • About
    • General information
    • Staff
    • Editorial Board
    • Contact
  • Subscribe to our alerts
  • RSS feeds
  • Follow JPN on Twitter
CRSN Symposium: Focus on Schizophrenia

Postmortem investigations of the pathophysiology of schizophrenia: the role of susceptibility genes

William R. Perlman, Cynthia Shannon Weickert, Mayada Akil and Joel E. Kleinman
J Psychiatry Neurosci July 01, 2004 29 (4) 287-293;
William R. Perlman
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Md.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cynthia Shannon Weickert
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Md.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mayada Akil
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Md.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joel E. Kleinman
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Md.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Tables
  • Responses
  • Metrics
  • PDF
Loading

Abstract

Despite robust evidence for the heritability of schizophrenia, postmortem studies have not traditionally linked cellular and molecular neuropathology with underlying genetic mechanisms in this disorder. The completion of the first draft of the Human Genome Project and the use of novel strategies in studying complex genetic disorders including schizophrenia have led to the identification of a growing list of schizophrenia susceptibility genes. In this review, we describe the strategy used to incorporate 2 potential schizophrenia susceptibility genes in the postmortem investigation of the pathophysiology of schizophrenia driven by 2 well-established hypotheses, the dopamine hypothesis and the neurodevelopmental hypothesis. The first gene codes for catechol-O-methyltransferase, an enzyme involved in catecholamine degradation, and the second gene codes for brain-derived neurotrophic factor, a growth factor implicated in cell survival, synaptogenesis and the development of cortical pyramidal neurons.

Introduction

Schizophrenia is a neuropsychiatric disorder characterized by hallucinations, delusions, thought disorder, deficit symptoms and cognitive dysfunction, with symptoms typically manifesting themselves in adolescence and early adulthood.1 Studies of the pathophysiology of this disorder have focused on the heritability of schizophrenia, the affected neurotransmitter systems and neuroanatomical abnormalities. A number of relatively consistent findings have emerged from these approaches. First, twin concordance rates, adoption studies, and genetic linkage and association analyses strongly suggest that schizophrenia has a heritable component.2,3 Second, the neurotransmitters dopamine (DA) and glutamate have been implicated through pharmacologic interventions that either mimic or exacerbate (N-methyl-d-aspartate [NMDA] receptor antagonists) or reduce (DA receptor antagonists) psychotic symptoms of schizophrenia. 4–7 Third, structural abnormalities in the brain include increased ventricular size along with reduced brain volume in the dorsolateral prefrontal cortex (DLPFC) and the entorhinal cortex, hippocampus and thalamus8–12 of patients with schizophrenia. The function of the DLPFC is also affected in schizophrenia, as demonstrated by decreased activation during the performance of cognitive tasks that are impaired in this disorder.13,14

Postmortem studies of schizophrenia have been hampered by a host of confounding variables. Although it is possible to match experimental subjects on the basis of gender, ethnic origin and postmortem interval (PMI), or time since death, other variables are more difficult to control. These include agonal state, ambient temperature after death and the accurate calculation of PMI. Moreover, the assumption that patients with schizophrenia and healthy controls can be matched ignores the higher incidence of alcohol and substance abuse in patients with schizophrenia, the consequences of a lifetime of treatment with neuroleptics and other drugs, the stress of acute exacerbations of illness and admissions to hospital, and the effects of a chronic mental illness on quality of life.15 On the other hand, postmortem studies allow a level of resolution not yet available through the use of imaging approaches and are invaluable in elucidating the pathophysiology of this disorder.

The completion of the first draft of the Human Genome Project followed by the discovery of allelic variants has presented schizophrenia researchers with an opportunity to link heredity to neurochemistry and neuroanatomy. It also allows genotyping of subjects with schizophrenia and controls, so that we can further elucidate the role of genes in systems of interest and refine the design of postmortem studies. Several strategies have been used in the study of the role of genes in schizophrenia. One approach is a top-down strategy, initially targeting large chromosomal loci implicated in schizophrenia by linkage analyses,16,17 with subsequent study of single nucleotide polymorphisms (SNPs) or groups of SNPs (haplotypes) within the implicated region. These SNPs and haplotypes are then examined in clinical association studies to determine whether they are associated with schizophrenia itself or intermediate phenotypes of the disorder. If so, then a gene can presumably be identified that contains the associated SNP or haplotype. Currently, at least 8 genes have been identified as schizophrenia susceptibility genes. Several of the genes under investigation as schizophrenia susceptibility genes are involved in glutamatergic signalling (G72, DAAO, RGS4 and NRG1),18 providing a link between hypotheses generated from imaging and neuropathologic studies and modern genetic approaches. Another gene implicated in schizophrenia by linkage analysis and involved in neurotransmission, the α–7 nicotinic acetylcholine receptor subunit gene (CHRNA7), has been identified as a schizophrenia susceptibility gene based on polymorphisms in the promoter region that appear more frequently in patients with schizophrenia as compared with unaffected controls. 19 In addition to genes involved in neurotransmission, a growing number of genes implicated in synapse formation, maintenance and plasticity have emerged as schizophrenia susceptibility genes. This list includes the aforementioned NRG1,20 as well as DTNBP121 and brain-derived neurotrophic factor (BDNF).22,23 Surely the list of schizophrenia susceptibility genes will continue to grow; the question is, however, how can we understand the functional implications of a susceptibility gene product on neurobiology in order to elucidate the pathophysiology of schizophrenia and eventually develop successful treatments? In this manuscript, we will describe the strategy we have used in the study of 2 genes in an attempt to link genetic vulnerability to the neurobiology of schizophrenia. The first gene codes for a DA-metabolizing enzyme catechol-O-methyltransferase (COMT), which was recently added to the list of schizophrenia susceptibility genes based on the discovery of an association between a haplotype of COMT and schizophrenia.24 A common SNP in this DA-metabolizing enzyme alters enzymatic activity and has functional implications for both cortical function and dopaminergic neurotransmission. The second gene examined is the gene for BDNF. At present, the status of the BDNF gene as a schizophrenia susceptibility gene is controversial; however, BDNF is an important neurotrophic factor for cortical glutamatergic pyramidal neurons and may play a role in synaptic pathology observed in the syndrome. More importantly, BDNF expression is known to be altered in schizophrenia25–27 and, therefore, if it is not itself a susceptibility gene, it is likely to be a downstream target of such a gene.

COMT

The COMT gene provides an excellent example of the use of new genetic information to understand an old hypothesis (the DA hypothesis of schizophrenia). The protein product of the COMT gene is an enzyme that catabolizes DA. Recently, COMT has been shown to contain a functional polymorphism resulting from a Val→Met substitution at the 108/158 locus in the peptide sequence. The Val allele substitution increases the efficiency of the enzyme 4-fold in comparison with the Met allele.28 On the basis of differential enzymatic activity, Val/Val individuals are expected to have decreased synaptic DA levels in the prefrontal cortex (PFC), Met/Met individuals to have high DA levels and Val/Met individuals to have intermediate DA levels. In imaging studies of healthy controls, this difference in COMT genotype has been shown to affect PFC function29–32 during working memory and other cognitive tasks known to depend on PFC DA levels. Patients with schizophrenia perform poorly on these cognitive tasks,33–35 and their PFC is not normally activated during performance of these tasks.33,35–38 These functional abnormalities have been related to cortical DA activity in in-vivo studies, 36,39–41 and the dopaminergic innervation of the PFC in schizophrenia is reduced.42 Last, inheriting a COMT Val allele has been found in association studies to increase the risk for schizophrenia slightly,29,43–45 implicating COMT as a susceptibility gene for schizophrenia. Thus, this COMT polymorphism, a susceptibility gene for schizophrenia, alters performance in healthy controls on a task that is known to depend upon DA levels in the PFC and is impaired in this disorder.

Dopaminergic signalling in schizophrenia is altered not only in the PFC but in subcortical structures such as the striatum as well. Dopaminergic tone in the PFC has indirect downstream effects on mesencephalic DA neurons. 46–48 A possible explanation for the relation between PFC excitatory cortical neurons and mesencephalic DA neurons has emerged from rodent experiments.49 In this proposed mechanism, prefrontal neurons tonically inhibit striatal DA projections, presumably through γ-aminobutyric acid (GABA)-ergic interneurons (Fig. 1).48,50,51 This model predicts that decreased PFC DA tone will result in a lessening of indirect tonic inhibition of mesencephalic DA neurons and, consequently, DA release from the mesencephalic neurons projecting to the striatum. Animal studies have substantiated this model,52,53 which provides a parsimonious explanation for the coexistence of cortical hypodopaminergia and subcortical hyperdopaminergia in schizophrenia.36,54,55

Fig. 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 1

Diagram of proposed circuitry and its role in the effects of the catechol-O-methyltransferase (COMT) genotype on tyrosine hydroxylase (TH) gene expression in the brain stem. We predict that the Val/Val genotype of the COMT enzyme leads to reduced dopamine (DA) levels in the prefrontal cortex (PFC) relative to the Val/Met genotype and that indirect PFC projections via γ-aminobutyric acid (GABA) neurons in the striatum or mesencephalon lead to increased gene expression of TH mRNA in DA cell groups projecting subcortically. Some of the GABA projections remain to be confirmed; see question mark. SN = substantia nigra, VTA = ventral tegmental area. Figure adapted with permission from the Society for Neuroscience (J Neurosci 2003;23:2008–13).51

If this COMT polymorphism alters DA levels in the PFC, does it also influence subcortical DA? One would predict that inheritance of a Val allele, which is associated with increased COMT enzymatic activity, presumably leading to decreased DA levels in the PFC, would result in relatively increased recruitment of mesencephalic DA activity. To test this hypothesis, using in situ hybridization, we examined the expression of mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme for DA biosynthesis, in 5 mesencephalic DA cell groups in postmortem human brain specimens from healthy subjects carrying the Val/Val or the Val/Met genotypes.51 In addition, we examined the expression of dopamine transporter (DAT) mRNA and cyclophilin mRNA as controls for DA-related and DA-unrelated genes, respectively, in the same cell groups. A significant main effect of genotype on TH mRNA levels was found in the dorsal and ventral tiers of the substantia nigra pars compacta (SND and SNV, respectively). There was no effect of genotype on DAT or cyclophilin mRNA expression. The SNV and SND in nonhuman primates project to the striatum and amygdala, 46 suggesting that the effects of the COMT genotype on TH regulation are greatest in cell groups that do not project back to the PFC. Our results are consistent with the theoretical model outlined earlier and suggest a mechanism by which the COMT Val allele increases risk for schizophrenia (decreased DA signalling in PFC and increased DA signalling subcortically).

In summary, we were able to use postmortem studies to elucidate some of the biologic effects of COMT polymorphisms on the circuitry involved in schizophrenia.

BDNF

The gene for BDNF has been reported to be a schizophrenia susceptibility gene,22,23 and some association studies suggest that inheritance of certain BDNF alleles may relate to age of onset of the disease, responsiveness to treatment and parietal lobe volume in patients with schizophrenia.56,57 However, no clear association with the clinical diagnosis of schizophrenia was found in a number of studies.56–61 It is important to note that further study of genetic association of allelic variation in the BDNF gene with schizophrenia is required before a determination can be made as to whether or not BDNF is a schizophrenia susceptibility gene.

Reductions in BDNF mRNA25–27 and protein27 in the PFC of patients with schizophrenia, which cannot be readily explained by allelic variation in the BDNF gene itself, have been recently described in separate cohorts. These data suggest that the BDNF gene may be an important downstream target of one or more schizophrenia susceptibility genes. Therefore, future studies of the role of BDNF in schizophrenia should explore the relation between the genotypes of the schizophrenia susceptibility gene(s) under investigation and BDNF expression levels. Similarly, other genes shown to display reliable alterations in mRNA or protein expression in patients with schizophrenia should be examined as potential targets of schizophrenia susceptibility genes.

As previously described, one of the prevailing hypotheses concerning the pathophysiology of schizophrenia involves abnormalities in glutamatergic signalling. Patients with schizophrenia demonstrate cortical glutamate dysfunction as evidenced by a reduction in both glutamate and a neurochemical marker of glutamatergic neuronal integrity, N-acetyl-aspartate.62–65 Recent evidence points to synaptic pathology as a possible component of glutamatergic dysfunction in the cortex of patients with schizophrenia. Glutamatergic neurons in the DLPFC of patients with schizophrenia show a reduction of mRNAs encoding presynaptic proteins,66–68 as well as a reduction in synapse-associated proteins.69–72 Both the density of dendritic spines in layer III pyramidal neurons73,74 and the cortical neuropil are reduced in the DLPFC of patients with schizophrenia, the latter relating to increased neuronal density and decreased soma size of pyramidal neurons.75–78 Upregulation of BDNF increases both neuronal size and synaptic density, making it an excellent candidate for investigation in schizophrenia.79

BDNF is synthesized by neurons in the rodent frontal cortex80–84 and by pyramidal neurons in the DLPFC of primates, including humans.27,85,86 This neurotrophin is a trophic factor for glutamatergic neurons, as evidenced by increases in cell survival in vitro87–89 and stimulation of the growth of dendrites and increases in spine density of glutamatergic pyramidal neurons in the neocortex.90,91 In addition to synthesis and release in response to afferent activity, BDNF also modulates synaptic density and long-term potentiation of glutamatergic cortical neurons.89–95 Last, BDNF is critical for the formation of excitatory synapses, as evidenced by in-vivo temporal contiguity between increases in cortical BDNF mRNA and cortical neuron dendrite growth and synapse formation.96–102

We recently tested the hypothesis that glutamate-related pathology in the brain of patients with schizophrenia is associated with abnormal BDNF expression in the DLPFC.27 Using quantitative Western blotting, RNase protection assays and in situ hybridization, we detected a reduction in both BDNF protein and mRNA in postmortem specimens from patients with schizophrenia as compared with matched healthy controls. BDNF mRNA was localized to pyramidal neurons throughout layers II, III, V and VI, with patients with schizophrenia showing a reduction in BDNF expression in layers III, V and VI, suggesting that these neurons may provide less trophic support to their targets. In support of the mRNA data, quantitative Western blotting revealed a 40% reduction in BDNF protein in patients with schizophrenia as compared with healthy controls. With careful attention to experimental design, we were able to test for the effects of age, PMI, neuroleptic treatment history and history of depression, all of which may influence BDNF mRNA levels.84,101,103–109 Because BDNF exerts potent effects on forebrain systems believed to be involved in schizophrenia, our results further our understanding of glutamatergic dysfunction in schizophrenia and provide new avenues of research in synaptic pathology. Our results, coupled with the possible association of the BDNF gene with schizophrenia, raise the important question of how inheritance of certain forms of the BDNF gene may affect BDNF gene expression or BDNF functions within the DLPFC and how this, in turn, may confer increased risk for schizophrenia.

Conclusion

The addition of a genetic component to the existing neuropathologic approach to understanding the pathophysiology of schizophrenia has far-reaching implications. We now have the tools required to subtype experimental subjects genetically, thereby eliminating a heretofore uncontrolled-for confounding variable inherent in postmortem studies. By understanding which allelic variants of genes such as COMT are more often associated with schizophrenia, experiments can focus on specific gene products and, potentially, on interacting gene products or biologic pathways. In this way, information can be generated implicating specific proteins, cell populations, neural circuits and neuroanatomical structures altered in schizophrenia. The identification of these genetic susceptibilities may ultimately lead to clinical interventions with an emphasis on developing more effective treatments for this debilitating disorder.

Footnotes

  • Medical subject headings: brain-derived neurotrophic factor; catechol-O-methyltransferase; dopamine; genetic predisposition to disease; glutamate; prefrontal cortex; schizophrenia; substantia nigra; tyrosine hydroxylase.

  • Competing interests: None declared.

  • Received July 4, 2003.
  • Revision received February 4, 2004.
  • Accepted February 17, 2004.

References

  1. ↵
    1. Lewis DA,
    2. Lieberman JA
    . Catching up on schizophrenia: natural history and neurobiology. Neuron 2000;28:325–34.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Gottesman I
    . Schizophrenia genesis: the origins of madness. New York: Freeman; 1991.
  3. ↵
    1. Pulver AE
    . Search for schizophrenia susceptibility genes. Biol Psychiatry 2000;47:221–30.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Allen RM,
    2. Young SJ
    . Phencyclidine-induced psychosis. Am J Psychiatry 1978;135:1081–4.
    OpenUrlCrossRefPubMed
    1. Javitt DC
    . Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia. Hillside J Clin Psychiatry 1987;9:12–35.
    OpenUrlPubMed
    1. Carlsson A
    . The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1988;1:179–86.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Deutsch SI,
    2. Mastropaolo J,
    3. Schwartz BL,
    4. Rosse RB,
    5. Morihisa JM
    . A “glutamatergic hypothesis” of schizophrenia. Rationale for pharmacotherapy with glycine. Clin Neuropharmacol 1989;12:1–13.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Suddath RL,
    2. Christison GW,
    3. Torrey EF,
    4. Casanova MF,
    5. Weinberger DR
    . Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 1990; 322:789–94.
    OpenUrlCrossRefPubMed
    1. Andreasen NC,
    2. Arndt S,
    3. Swayze V 2nd.,
    4. Cizadlo T,
    5. Flaum M,
    6. O’Leary D,
    7. et al
    . Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 1994;266:294–8.
    OpenUrlAbstract/FREE Full Text
    1. Chua SE,
    2. McKenna PJ
    . Schizophrenia—a brain disease? A critical review of structural and functional cerebral abnormality in the disorder. Br J Psychiatry 1995;166:563–82.
    OpenUrlAbstract/FREE Full Text
    1. Kotrla KJ,
    2. Weinberger DR
    . Brain imaging in schizophrenia. Annu Rev Med 1995;46:113–22.
    OpenUrlCrossRefPubMed
  7. ↵
    1. McCarley RW,
    2. Wible CG,
    3. Frumin M,
    4. Hirayasu Y,
    5. Levitt JJ,
    6. Fischer IA,
    7. et al
    . MRI anatomy of schizophrenia. Biol Psychiatry 1999;45:1099–119.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Berman KF,
    2. Torrey EF,
    3. Daniel DG,
    4. Weinberger DR
    . Regional cerebral blood flow in monozygotic twins discordant and concordant for schizophrenia. Arch Gen Psychiatry 1992;49:927–34.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Weinberger DR,
    2. Berman KF,
    3. Suddath R,
    4. Torrey EF
    . Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry 1992;149:890–7.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Lewis DA,
    2. Akil M
    . Cortical dopamine in schizophrenia: strategies for postmortem studies. J Psychiatr Res 1997;31:175–95.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Badner JA,
    2. Gershon ES
    . Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002;7:405–11.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Levinson D,
    2. Lewis C,
    3. Wise L
    . Meta-analysis of genome scans for schizophrenia. Am J Med Genet 2002;114:700–1.
    OpenUrl
  13. ↵
    1. Harrison PJ,
    2. Owen MJ
    . Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003;361:417–9.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Leonard S,
    2. Gault J,
    3. Hopkins J,
    4. Logel J,
    5. Vianzon R,
    6. Short M,
    7. et al
    . Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry 2002;59:1085–96.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Stefansson H,
    2. Sigurdsson E,
    3. Steinthorsdottir V,
    4. Bjornsdottir S,
    5. Sigmundsson T,
    6. Ghosh S,
    7. et al
    . Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002;71:877–92.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Straub RE,
    2. Jiang Y,
    3. MacLean CJ,
    4. Ma Y,
    5. Webb BT,
    6. Myakishev MV,
    7. et al
    . Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002;71:337–48.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Muglia P,
    2. Vicente AM,
    3. Verga M,
    4. King N,
    5. Macciardi F,
    6. Kennedy JL
    . Association between the BDNF gene and schizophrenia. Mol Psychiatry 2003;8:146–7.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Szekeres G,
    2. Juhasz A,
    3. Rimanoczy A,
    4. Keri S,
    5. Janka Z
    . The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia. Schizophr Res 2003;65:15–8.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Shifman S,
    2. Bronstein M,
    3. Sternfeld M,
    4. Pisante-Shalom A,
    5. Lev-Lehman E,
    6. Weizman A,
    7. et al
    . A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002;71:1296–302.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Hashimoto T,
    2. Volk DW,
    3. Buchheit SE,
    4. Lewis DA
    . Expression of BDNF and TrkB mRNAs in prefrontal cortex of subjects with schizophrenia (poster). Program no. 703.7. 2002 Abstract Viewer/Itinerary Planner. Washington: Society for Neuroscience; 2002. Available: http://sfn.scholarone.com/itin2002/index.html (accessed 2004 June 8).
    1. Webster MJ,
    2. Wyatt EJ,
    3. Kleinman JE,
    4. Weickert CS
    . BDNF and TrkB mRNA levels in the prefrontal cortex and hippocampus of individuals with major mental illness (poster). Program no. 703.7. 2003 Abstract Viewer/Itinerary Planner. Washington: Society for Neuroscience; 2003. Available: http://sfn.scholarone.com/itin2003/index.html (accessed 2004 June 8).
  21. ↵
    1. Weickert CS,
    2. Hyde TM,
    3. Lipska BK,
    4. Herman MM,
    5. Weinberger DR,
    6. Kleinman JE
    . Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 2003;8:592–610.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Mannisto PT,
    2. Kaakkola S
    . Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 1999;51:593–628.
    OpenUrlFREE Full Text
  23. ↵
    1. Egan MF,
    2. Goldberg TE,
    3. Kolachana BS,
    4. Callicott JH,
    5. Mazzanti CM,
    6. Straub RE,
    7. et al
    . Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 2001;98:6917–22.
    OpenUrlAbstract/FREE Full Text
    1. Rosa A,
    2. Zarzuela A,
    3. Cuesta M,
    4. Peralta V,
    5. Martinez-Larrea A,
    6. Serrano F,
    7. et al
    . New evidence for association between COMT gene and prefrontal neurocognitive functions in schizophrenia. Schizophr Res 2002;53(Suppl):69.
    OpenUrl
    1. Bilder RM,
    2. Volavka J,
    3. Czobor P,
    4. Malhotra AK,
    5. Kennedy JL,
    6. Ni X,
    7. et al
    . Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry 2002;52:701–7.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Malhotra AK,
    2. Kestler LJ,
    3. Mazzanti C,
    4. Bates JA,
    5. Goldberg T,
    6. Goldman D
    . A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 2002;159:652–4.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Weinberger DR,
    2. Berman KF,
    3. Zec RF
    . Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry 1986;43:114–24.
    OpenUrlCrossRefPubMed
    1. Park S,
    2. Holzman PS
    . Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry 1992;49:975–82.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Carter CS,
    2. Perlstein W,
    3. Ganguli R,
    4. Brar J,
    5. Mintun M,
    6. Cohen JD
    . Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry 1998;155:1285–7.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Weinberger DR,
    2. Berman KF,
    3. Illowsky BP
    . Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry 1988;45:609–15.
    OpenUrlCrossRefPubMed
    1. Callicott JH,
    2. Bertolino A,
    3. Mattay VS,
    4. Langheim FJ,
    5. Duyn J,
    6. Coppola R,
    7. et al
    . Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex 2000; 10:1078–92.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Barch DM,
    2. Carter CS,
    3. Braver TS,
    4. Sabb FW,
    5. MacDonald A 3rd.,
    6. Noll DC,
    7. et al
    . Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch Gen Psychiatry 2001;58:280–8.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Daniel DG,
    2. Weinberger DR,
    3. Jones DW,
    4. Zigun JR,
    5. Coppola R,
    6. Handel S,
    7. et al
    . The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia. J Neurosci 1991;11:1907–17.
    OpenUrlAbstract/FREE Full Text
    1. Okubo Y,
    2. Suhara T,
    3. Suzuki K,
    4. Kobayashi K,
    5. Inoue O,
    6. Terasaki O,
    7. et al
    . Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 1997;385:634–6.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Abi-Dargham A,
    2. Mawlawi O,
    3. Lombardo I,
    4. Gil R,
    5. Martinez D,
    6. Huang Y,
    7. et al
    . Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002;22:3708–19.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Akil M,
    2. Pierri JN,
    3. Whitehead RE,
    4. Edgar CL,
    5. Mohila C,
    6. Sampson AR,
    7. et al
    . Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry 1999;156:1580–9.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Li T,
    2. Sham PC,
    3. Vallada H,
    4. Xie T,
    5. Tang X,
    6. Murray RM,
    7. et al
    . Preferential transmission of the high activity allele of COMT in schizophrenia. Psychiatr Genet 1996;6:131–3.
    OpenUrlPubMed
    1. Li T,
    2. Ball D,
    3. Zhao J,
    4. Murray RM,
    5. Liu X,
    6. Sham PC,
    7. et al
    . Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 2000;5:77–84.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Kunugi H,
    2. Vallada HP,
    3. Sham PC,
    4. Hoda F,
    5. Arranz MJ,
    6. Li T,
    7. et al
    . Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet 1997;7:97–101.
    OpenUrlPubMed
  34. ↵
    1. Haber SN,
    2. Fudge JL
    . The primate substantia nigra and VTA: integrative circuitry and function. Crit Rev Neurobiol 1997;11:323–42.
    OpenUrlCrossRefPubMed
    1. Lu XY,
    2. Churchill L,
    3. Kalivas PW
    . Expression of D1 receptor mRNA in projections from the forebrain to the ventral tegmental area. Synapse 1997;25:205–14.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Carr DB,
    2. Sesack SR
    . Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci 2000;20:3864–73.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Pycock CJ,
    2. Carter CJ,
    3. Kerwin RW
    . Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on neurotransmitter systems in subcortical sites in the rat. J Neurochem 1980;34:91–9.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Carlsson A
    . A paradigm shift in brain research. Science 2001; 294:1021–4.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Akil M,
    2. Kolachana BS,
    3. Rothmond DA,
    4. Hyde TM,
    5. Weinberger DR,
    6. Kleinman JE
    . Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 2003;23: 2008–13.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Kolachana BS,
    2. Saunders RC,
    3. Weinberger DR
    . Augmentation of prefrontal cortical monoaminergic activity inhibits dopamine release in the caudate nucleus: an in vivo neurochemical assessment in the rhesus monkey. Neuroscience 1995;69:859–68.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Harden DG,
    2. King D,
    3. Finlay JM,
    4. Grace AA
    . Depletion of dopamine in the prefrontal cortex decreases the basal electrophysiological activity of mesolimbic dopamine neurons. Brain Res 1998;794:96–102.
    OpenUrlCrossRefPubMed
  41. ↵
    1. Weinberger DR
    . Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44:660–9.
    OpenUrlCrossRefPubMed
  42. ↵
    1. Grace AA
    . Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Brain Res Rev 2000;31:330–41.
    OpenUrlCrossRefPubMed
  43. ↵
    1. Wassink TH,
    2. Nelson JJ,
    3. Crowe RR,
    4. Andreasen NC
    . Heritability of BDNF alleles and their effect on brain morphology in schizophrenia. Am J Med Genet 1999;88:724–8.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Krebs MO,
    2. Guillin O,
    3. Bourdell MC,
    4. Schwartz JC,
    5. Olie JP,
    6. Poirier MF,
    7. et al
    . Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol Psychiatry 2000;5:558–62.
    OpenUrlCrossRefPubMed
    1. Sasaki T,
    2. Dai XY,
    3. Kuwata S,
    4. Fukuda R,
    5. Kunugi H,
    6. Hattori M,
    7. et al
    . Brain-derived neurotrophic factor gene and schizophrenia in Japanese subjects. Am J Med Genet 1997;74:443–4.
    OpenUrlPubMed
    1. Hawi Z,
    2. Straub RE,
    3. O’Neill A,
    4. Kendler KS,
    5. Walsh D,
    6. Gill M
    . No linkage or linkage disequilibrium between brain-derived neurotrophic factor (BDNF) dinucleotide repeat polymorphism and schizophrenia in Irish families. Psychiatry Res 1998;81:111–6.
    OpenUrlCrossRefPubMed
    1. Virgos C,
    2. Martorell L,
    3. Valero J,
    4. Figuera L,
    5. Civeira F,
    6. Joven J,
    7. et al
    . Association study of schizophrenia with polymorphisms at six candidate genes. Schizophr Res 2001;49:65–71.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Egan MF,
    2. Kojima M,
    3. Callicott JH,
    4. Goldberg TE,
    5. Kolachana BS,
    6. Bertolino A,
    7. et al
    . The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003;112:257–69.
    OpenUrlCrossRefPubMed
  46. ↵
    1. Tsai G,
    2. Passani LA,
    3. Slusher BS,
    4. Carter R,
    5. Baer L,
    6. Kleinman JE,
    7. et al
    . Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Arch Gen Psychiatry 1995;52:829–36.
    OpenUrlCrossRefPubMed
    1. Bertolino A,
    2. Nawroz S,
    3. Mattay VS,
    4. Barnett AS,
    5. Duyn JH,
    6. Moonen CT,
    7. et al
    . Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry 1996;153:1554–63.
    OpenUrlCrossRefPubMed
    1. Bertolino A,
    2. Callicott JH,
    3. Elman I,
    4. Mattay VS,
    5. Tedeschi G,
    6. Frank JA,
    7. et al
    . Regionally specific neuronal pathology in untreated patients with schizophrenia: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry 1998;43:641–8.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Block W,
    2. Bayer TA,
    3. Tepest R,
    4. Traber F,
    5. Rietschel M,
    6. Muller DJ,
    7. et al
    . Decreased frontal lobe ratio of N-acetyl aspartate to choline in familial schizophrenia: a proton magnetic resonance spectroscopy study. Neurosci Lett 2000;289:147–51.
    OpenUrlCrossRefPubMed
  48. ↵
    1. Mirnics K,
    2. Middleton FA,
    3. Marquez A,
    4. Lewis DA,
    5. Levitt P
    . Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 2000;28:53–67.
    OpenUrlCrossRefPubMed
    1. Weickert CS,
    2. Webster MJ,
    3. Hyde TM,
    4. Herman MM,
    5. Bachus SE,
    6. Bali G,
    7. et al
    . Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia. Cereb Cortex 2001;11:136–47.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Vawter MP,
    2. Crook JM,
    3. Hyde TM,
    4. Kleinman JE,
    5. Weinberger DR,
    6. Becker KG,
    7. et al
    . Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: a preliminary study. Schizophr Res 2002;58:11–20.
    OpenUrlCrossRefPubMed
  50. ↵
    1. Glantz LA,
    2. Lewis DA
    . Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity. Arch Gen Psychiatry 1997;54:660–9.
    OpenUrlCrossRefPubMed
    1. Thompson PM,
    2. Sower AC,
    3. Perrone-Bizzozero NI
    . Altered levels of the synaptosomal associated protein SNAP-25 in schizophrenia. Biol Psychiatry 1998;43:239–43.
    OpenUrlCrossRefPubMed
    1. Honer WG,
    2. Falkai P,
    3. Chen C,
    4. Arango V,
    5. Mann JJ,
    6. Dwork AJ
    . Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness. Neuroscience 1999;91:1247–55.
    OpenUrlCrossRefPubMed
  51. ↵
    1. Karson CN,
    2. Mrak RE,
    3. Schluterman KO,
    4. Sturner WQ,
    5. Sheng JG,
    6. Griffin WS
    . Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for ‘hypofrontality’. Mol Psychiatry 1999;4:39–45.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Garey LJ,
    2. Ong WY,
    3. Patel TS,
    4. Kanani M,
    5. Davis A,
    6. Mortimer AM,
    7. et al
    . Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 1998;65:446–53.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    1. Glantz LA,
    2. Lewis DA
    . Dendritic spine density in schizophrenia and depression. Arch Gen Psychiatry 2001;58:203.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Selemon LD,
    2. Rajkowska G,
    3. Goldman-Rakic PS
    . Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 1995;52:805–18; discussion 819–20.
    OpenUrlCrossRefPubMed
    1. Selemon LD,
    2. Rajkowska G,
    3. Goldman-Rakic PS
    . Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional, stereologic counting method. J Comp Neurol 1998;392:402–12.
    OpenUrlCrossRefPubMed
    1. Rajkowska G,
    2. Selemon LD,
    3. Goldman-Rakic PS
    . Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 1998;55:215–24.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Pierri JN,
    2. Volk CL,
    3. Auh S,
    4. Sampson A,
    5. Lewis DA
    . Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia. Arch Gen Psychiatry 2001;58:466–73.
    OpenUrlCrossRefPubMed
  56. ↵
    1. Weickert CS,
    2. Kleinman JE
    . The neuroanatomy and neurochemistry of schizophrenia. Psychiatr Clin North Am 1998;21:57–75.
    OpenUrlCrossRefPubMed
  57. ↵
    1. Hofer M,
    2. Pagliusi SR,
    3. Hohn A,
    4. Leibrock J,
    5. Barde YA
    . Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J 1990;9:2459–64.
    OpenUrlPubMed
    1. Wetmore C,
    2. Ernfors P,
    3. Persson H,
    4. Olson L
    . Localization of brain-derived neurotrophic factor mRNA to neurons in the brain by in situ hybridization. Exp Neurol 1990;109:141–52.
    OpenUrlCrossRefPubMed
    1. Phillips HS,
    2. Hains JM,
    3. Armanini M,
    4. Laramee GR,
    5. Johnson SA,
    6. Winslow JW
    . BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 1991;7:695–702.
    OpenUrlCrossRefPubMed
    1. Friedman WJ,
    2. Black IB,
    3. Kaplan DR
    . Distribution of the neurotrophins brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 in the postnatal rat brain: an immunocytochemical study. Neuroscience 1998;84:101–14.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Lipska BK,
    2. Khaing ZZ,
    3. Weickert CS,
    4. Weinberger DR
    . BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs. Eur J Neurosci 2001;14:135–44.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Huntley GW,
    2. Benson DL,
    3. Jones EG,
    4. Isackson PJ
    . Developmental expression of brain derived neurotrophic factor mRNA by neurons of fetal and adult monkey prefrontal cortex. Brain Res Dev Brain Res 1992;70:53–63.
    OpenUrlCrossRefPubMed
  60. ↵
    1. Webster MJ,
    2. Weickert CS,
    3. Herman MM,
    4. Kleinman JE
    . BDNF mRNA expression during postnatal development, maturation and aging of the human prefrontal cortex. Brain Res Dev Brain Res 2002;139:139–50.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Lindholm D,
    2. Dechant G,
    3. Heisenberg CP,
    4. Thoenen H
    . Brain-derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity. Eur J Neurosci 1993;5:1455–64.
    OpenUrlCrossRefPubMed
    1. Cheng B,
    2. Mattson MP
    . NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res 1994;640:56–67.
    OpenUrlCrossRefPubMed
  62. ↵
    1. Ghosh A,
    2. Carnahan J,
    3. Greenberg ME
    . Requirement for BDNF in activity-dependent survival of cortical neurons. Science 1994;263:1618–23.
    OpenUrlAbstract/FREE Full Text
  63. ↵
    1. McAllister AK,
    2. Lo DC,
    3. Katz LC
    . Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 1995;15:791–803.
    OpenUrlCrossRefPubMed
  64. ↵
    1. McAllister AK,
    2. Katz LC,
    3. Lo DC
    . Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 1996;17:1057–64.
    OpenUrlCrossRefPubMed
    1. Zafra F,
    2. Hengerer B,
    3. Leibrock J,
    4. Thoenen H,
    5. Lindholm D
    . Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J 1990;9:3545–50.
    OpenUrlPubMed
    1. Gwag BJ,
    2. Springer JE
    . Activation of NMDA receptors increases brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampal formation. Neuroreport 1993;5:125–8.
    OpenUrlCrossRefPubMed
    1. Kang H,
    2. Schuman EM
    . Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 1995;267:1658–62.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    1. Thoenen H
    . Neurotrophins and neuronal plasticity. Science 1995;270:593–8.
    OpenUrlAbstract/FREE Full Text
  66. ↵
    1. Maisonpierre PC,
    2. Belluscio L,
    3. Friedman B,
    4. Alderson RF,
    5. Wiegand SJ,
    6. Furth ME,
    7. et al
    . NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron 1990;5:501–9.
    OpenUrlCrossRefPubMed
    1. Friedman WJ,
    2. Ernfors P,
    3. Persson H
    . Transient and persistent expression of NT-3/HDNF mRNA in the rat brain during postnatal development. J Neurosci 1991;11:1577–84.
    OpenUrlAbstract/FREE Full Text
    1. Dugich-Djordjevic MM,
    2. Tocco G,
    3. Willoughby DA,
    4. Najm I,
    5. Pasinetti G,
    6. Thompson RF,
    7. et al
    . BDNF mRNA expression in the developing rat brain following kainic acid-induced seizure activity. Neuron 1992;8:1127–38.
    OpenUrlCrossRefPubMed
    1. Ringstedt T,
    2. Lagercrantz H,
    3. Persson H
    . Expression of members of the trk family in the developing postnatal rat brain. Brain Res Dev Brain Res 1993;72:119–31.
    OpenUrlPubMed
    1. Knusel B,
    2. Rabin SJ,
    3. Hefti F,
    4. Kaplan DR
    . Regulated neurotrophin receptor responsiveness during neuronal migration and early differentiation. J Neurosci 1994;14:1542–54.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    1. Katoh-Semba R,
    2. Takeuchi IK,
    3. Semba R,
    4. Kato K
    . Distribution of brain-derived neurotrophic factor in rats and its changes with development in the brain. J Neurochem 1997;69:34–42.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Itami C,
    2. Mizuno K,
    3. Kohno T,
    4. Nakamura S
    . Brain-derived neurotrophic factor requirement for activity-dependent maturation of glutamatergic synapse in developing mouse somatosensory cortex. Brain Res 2000;857:141–50.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Duman RS
    . Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 1998;44:324–35.
    OpenUrlCrossRefPubMed
    1. Angelucci F,
    2. Aloe L,
    3. Vasquez PJ,
    4. Mathe AA
    . Mapping the differences in the brain concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression. Neuroreport 2000;11:1369–73.
    OpenUrlCrossRefPubMed
    1. Linden AM,
    2. Vaisanen J,
    3. Lakso M,
    4. Nawa H,
    5. Wong G,
    6. Castren E
    . Expression of neurotrophins BDNF and NT-3, and their receptors in rat brain after administration of antipsychotic and psychotrophic agents. J Mol Neurosci 2000;14:27–37.
    OpenUrlCrossRefPubMed
    1. Takahashi M,
    2. Shirakawa O,
    3. Toyooka K,
    4. Kitamura N,
    5. Hashimoto T,
    6. Maeda K,
    7. et al
    . Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 2000;5:293–300.
    OpenUrlCrossRefPubMed
    1. Dawson NM,
    2. Hamid EH,
    3. Egan MF,
    4. Meredith GE
    . Changes in the pattern of brain-derived neurotrophic factor immunoreactivity in the rat brain after acute and subchronic haloperidol treatment. Synapse 2001;39:70–81.
    OpenUrlCrossRefPubMed
    1. Durany N,
    2. Michel T,
    3. Zochling R,
    4. Boissl KW,
    5. Cruz-Sanchez FF,
    6. Riederer P,
    7. et al
    . Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr Res 2001;52: 79–86.
    OpenUrlCrossRefPubMed
  70. ↵
    1. Vaidya VA,
    2. Duman RS
    . Depresssion—emerging insights from neurobiology. Br Med Bull 2001;57:61–79.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Journal of Psychiatry and Neuroscience: 29 (4)
J Psychiatry Neurosci
Vol. 29, Issue 4
1 Jul 2004
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author

Article tools

Respond to this article
Print
Download PDF
Article Alerts
To sign up for email alerts or to access your current email alerts, enter your email address below:
Email Article

Thank you for your interest in spreading the word on JPN.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Postmortem investigations of the pathophysiology of schizophrenia: the role of susceptibility genes
(Your Name) has sent you a message from JPN
(Your Name) thought you would like to see the JPN web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Postmortem investigations of the pathophysiology of schizophrenia: the role of susceptibility genes
William R. Perlman, Cynthia Shannon Weickert, Mayada Akil, Joel E. Kleinman
J Psychiatry Neurosci Jul 2004, 29 (4) 287-293;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
‍ Request Permissions
Share
Postmortem investigations of the pathophysiology of schizophrenia: the role of susceptibility genes
William R. Perlman, Cynthia Shannon Weickert, Mayada Akil, Joel E. Kleinman
J Psychiatry Neurosci Jul 2004, 29 (4) 287-293;
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Google Scholar

Similar Articles

Content

  • Current issue
  • Past issues
  • Collections
  • Alerts
  • RSS

Authors & Reviewers

  • Overview for Authors
  • Submit a manuscript
  • Manuscript Submission Checklist

About

  • General Information
  • Staff
  • Editorial Board
  • Contact Us
  • Advertising
  • Reprints
  • Copyright and Permissions
  • Accessibility
  • CMA Civility Standards
CMAJ Group

Copyright 2023, CMA Impact Inc. or its licensors. All rights reserved. ISSN 1180-4882.

All editorial matter in JPN represents the opinions of the authors and not necessarily those of the Canadian Medical Association or its subsidiaries.
To receive any of these resources in an accessible format, please contact us at CMAJ Group, 500-1410 Blair Towers Place, Ottawa ON, K1J 9B9; p: 1-888-855-2555; e: [email protected].
View CMA's Accessibility policy.

Powered by HighWire