This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (178)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • Bipolar Disorder  • Schizophrenia  • Alert me on articles by topic

A Postmortem Brain Study

Alessandro Guidotti, MD; James Auta, PhD; John M. Davis, MD; Valeria DiGiorgi Gerevini, PhD; Yogesh Dwivedi, PhD; Dennis R. Grayson, PhD; Francesco Impagnatiello, PhD; Ghanshyam Pandey, PhD; Christine Pesold, PhD; Rajiv Sharma, MD; Doncho Uzunov, PhD; Erminio Costa, MD

Arch Gen Psychiatry. 2000;57:1061-1069.

Background  Reelin (RELN) is a glycoprotein secreted preferentially by cortical -aminobutyric acid-ergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD)₆₇, but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects.

Methods  Reelin, GAD₆₅, GAD₆₇, DAB1, and neuron-specific–enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody.

Results  Prefrontal cortex and cerebellar expression of RELN mRNA, GAD₆₇ protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD₆₅ and neuron-specific–enolase expression implying that RELN and GAD₆₇ down-regulations were unrelated to neuronal damage. Reelin and GAD₆₇ were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication.

Conclusions  The selective down-regulation of RELN and GAD₆₇ in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis.

From the Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago. The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Altered Expression of Genes Involved in GABAergic Transmission and Neuromodulation of Granule Cell Activity in the Cerebellum of Schizophrenia Patients
Bullock et al.
Am. J. Psychiatry 2008;165:1594-1603.
ABSTRACT | FULL TEXT  

Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia
Lewis et al.
Am. J. Psychiatry 2008;165:1585-1593.
ABSTRACT | FULL TEXT  

From the Cover: Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons
Satta et al.
Proc. Natl. Acad. Sci. USA 2008;105:16356-16361.
ABSTRACT | FULL TEXT  

The Reelin Signaling Pathway Promotes Dendritic Spine Development in Hippocampal Neurons
Niu et al.
J. Neurosci. 2008;28:10339-10348.
ABSTRACT | FULL TEXT  

Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation
Dong et al.
Proc. Natl. Acad. Sci. USA 2008;105:13614-13619.
ABSTRACT | FULL TEXT  

GABA Neurons and the Mechanisms of Network Oscillations: Implications for Understanding Cortical Dysfunction in Schizophrenia
Gonzalez-Burgos and Lewis
Schizophr Bull 2008;34:944-961.
ABSTRACT | FULL TEXT  

Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex
Zhang et al.
J. Neurophysiol. 2008;100:959-965.
ABSTRACT | FULL TEXT  

Reduced Cortical Cannabinoid 1 Receptor Messenger RNA and Protein Expression in Schizophrenia
Eggan et al.
Arch Gen Psychiatry 2008;65:772-784.
ABSTRACT | FULL TEXT  

Alterations in Somatostatin mRNA Expression in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia or Schizoaffective Disorder
Morris et al.
Cereb Cortex 2008;18:1575-1587.
ABSTRACT | FULL TEXT  

Conserved Regional Patterns of GABA-Related Transcript Expression in the Neocortex of Subjects With Schizophrenia
Hashimoto et al.
Am. J. Psychiatry 2008;165:479-489.
ABSTRACT | FULL TEXT  

Insights from spatially mapped gene expression in the mouse brain
Sunkin and Hohmann
Hum Mol Genet 2007;16:R209-R219.
ABSTRACT | FULL TEXT  

Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal
Drew et al.
Hum Mol Genet 2007;16:2288-2305.
ABSTRACT | FULL TEXT  

Bipolar Disorder and Epilepsy: A Bidirectional Relation? Neurobiological Underpinnings, Current Hypotheses, and Future Research Directions
Mazza et al.
Neuroscientist 2007;13:392-404.
ABSTRACT  

Searching for Unique Endophenotypes for Schizophrenia and Bipolar Disorder Within Neural Circuits and Their Molecular Regulatory Mechanisms
Benes
Schizophr Bull 2007;33:932-936.
ABSTRACT | FULL TEXT  

Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters
Dong et al.
Proc. Natl. Acad. Sci. USA 2007;104:4676-4681.
ABSTRACT | FULL TEXT  

DNA Methyltransferase Inhibitors Coordinately Induce Expression of the Human Reelin and Glutamic Acid Decarboxylase 67 Genes
Kundakovic et al.
Mol. Pharmacol. 2007;71:644-653.
ABSTRACT | FULL TEXT  

Effects of {gamma}-Aminobutyric Acid-Modulating Drugs on Working Memory and Brain Function in Patients With Schizophrenia
Menzies et al.
Arch Gen Psychiatry 2007;64:156-167.
ABSTRACT | FULL TEXT  

Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder
Abdolmaleky et al.
Hum Mol Genet 2006;15:3132-3145.
ABSTRACT | FULL TEXT  

Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs
Lipska et al.
Hum Mol Genet 2006;15:1245-1258.
ABSTRACT | FULL TEXT  

From The Cover: The benzamide MS-275 is a potent, long-lasting brain region-selective inhibitor of histone deacetylases
Simonini et al.
Proc. Natl. Acad. Sci. USA 2006;103:1587-1592.
ABSTRACT | FULL TEXT  

A schizophrenia-related sensorimotor deficit links {alpha}3-containing GABAA receptors to a dopamine hyperfunction
Yee et al.
Proc. Natl. Acad. Sci. USA 2005;102:17154-17159.
ABSTRACT | FULL TEXT  

Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia
Dong et al.
Proc. Natl. Acad. Sci. USA 2005;102:12578-12583.
ABSTRACT | FULL TEXT  

Chromatin Alterations Associated With Down-regulated Metabolic Gene Expression in the Prefrontal Cortex of Subjects With Schizophrenia
Akbarian et al.
Arch Gen Psychiatry 2005;62:829-840.
ABSTRACT | FULL TEXT  

Reelin promoter hypermethylation in schizophrenia
Grayson et al.
Proc. Natl. Acad. Sci. USA 2005;102:9341-9346.
ABSTRACT | FULL TEXT  

In psychosis, cortical interneurons overexpress DNA-methyltransferase 1
Veldic et al.
Proc. Natl. Acad. Sci. USA 2005;102:2152-2157.
ABSTRACT | FULL TEXT  

DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures
Noh et al.
Proc. Natl. Acad. Sci. USA 2005;102:1749-1754.
ABSTRACT | FULL TEXT  

Relationship of Brain-Derived Neurotrophic Factor and Its Receptor TrkB to Altered Inhibitory Prefrontal Circuitry in Schizophrenia
Hashimoto et al.
J. Neurosci. 2005;25:372-383.
ABSTRACT | FULL TEXT  

Bipolar Disorder
Belmaker
NEJM 2004;351:476-486.
FULL TEXT  

Density of Glutamic Acid Decarboxylase 67 Messenger RNA-Containing Neurons That Express the N-Methyl-D-Aspartate Receptor Subunit NR2A in the Anterior Cingulate Cortex in Schizophrenia and Bipolar Disorder
Woo et al.
Arch Gen Psychiatry 2004;61:649-657.
ABSTRACT | FULL TEXT  

p73 and Reelin in Cajal-Retzius Cells of the Developing Human Hippocampal Formation
Abraham et al.
Cereb Cortex 2004;14:484-495.
ABSTRACT | FULL TEXT  

Molecular Evidence for Mitochondrial Dysfunction in Bipolar Disorder
Konradi et al.
Arch Gen Psychiatry 2004;61:300-308.
ABSTRACT | FULL TEXT  

DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains
Veldic et al.
Proc. Natl. Acad. Sci. USA 2004;101:348-353.
ABSTRACT | FULL TEXT  

Decreased Thalamic Expression of the Homeobox Gene DLX1 in Psychosis
Kromkamp et al.
Arch Gen Psychiatry 2003;60:869-874.
ABSTRACT | FULL TEXT  

Depression: What We can Learn from Postmortem Studies
Rajkowska
Neuroscientist 2003;9:273-284.
ABSTRACT  

Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia
Hashimoto et al.
J. Neurosci. 2003;23:6315-6326.
ABSTRACT | FULL TEXT  

Epigenetic Downregulation of GABAergic Function in Schizophrenia: Potential for Pharmacological Intervention?
Costa et al.
Mol. Interv. 2003;3:220-229.
ABSTRACT | FULL TEXT  

Lower Concentration of Hippocampal N-Acetylaspartate in Familial Bipolar I Disorder
Deicken et al.
Am. J. Psychiatry 2003;160:873-882.
ABSTRACT | FULL TEXT  

White Matter Changes in Schizophrenia: Evidence for Myelin-Related Dysfunction
Davis et al.
Arch Gen Psychiatry 2003;60:443-456.
ABSTRACT | FULL TEXT  

Recent Advances in the Neurobiology of Schizophrenia
Miyamoto et al.
Mol. Interv. 2003;3:27-39.
ABSTRACT | FULL TEXT  

From the Cover: Disrupted-in-Schizophrenia-1 (DISC-1): Mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth
Ozeki et al.
Proc. Natl. Acad. Sci. USA 2003;100:289-294.
ABSTRACT | FULL TEXT  

An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability
Tremolizzo et al.
Proc. Natl. Acad. Sci. USA 2002;99:17095-17100.
ABSTRACT | FULL TEXT  

Reelin Immunoreactivity in the Adult Primate Brain: Intracellular Localization in Projecting and Local Circuit Neurons of the Cerebral Cortex, Hippocampus and Subcortical Regions
Martinez-Cerdeno et al.
Cereb Cortex 2002;12:1298-1311.
ABSTRACT | FULL TEXT  

Reciprocal Alterations in Pre- and Postsynaptic Inhibitory Markers at Chandelier Cell Inputs to Pyramidal Neurons in Schizophrenia
Volk et al.
Cereb Cortex 2002;12:1063-1070.
ABSTRACT | FULL TEXT  

Implications for Altered Glutamate and GABA Metabolism in the Dorsolateral Prefrontal Cortex of Aged Schizophrenic Patients
Gluck et al.
Am. J. Psychiatry 2002;159:1165-1173.
ABSTRACT | FULL TEXT  

On the epigenetic regulation of the human reelin promoter
Chen et al.
Nucleic Acids Res 2002;30:2930-2939.
ABSTRACT | FULL TEXT  

The neuropathology of primary mood disorder
Harrison
Brain 2002;125:1428-1449.
ABSTRACT | FULL TEXT  

Differential Hippocampal Expression of Glutamic Acid Decarboxylase 65 and 67 Messenger RNA in Bipolar Disorder and Schizophrenia
Heckers et al.
Arch Gen Psychiatry 2002;59:521-529.
ABSTRACT | FULL TEXT  

Schizophrenia: Diverse Approaches to a Complex Disease
Sawa and Snyder
Science 2002;296:692-695.
ABSTRACT | FULL TEXT  

Reelin function in neural stem cell biology
Kim et al.
Proc. Natl. Acad. Sci. USA 2002;99:4020-4025.
ABSTRACT | FULL TEXT  

REELIN and Schizophrenia:: A Disease at the Interface of the Genome and the Epigenome
Costa et al.
Mol. Interv. 2002;2:47-57.
ABSTRACT | FULL TEXT  

Reelin Is a Serine Protease of the Extracellular Matrix
Quattrocchi et al.
J. Biol. Chem. 2002;277:303-309.
ABSTRACT | FULL TEXT  

Persistent reelin-expressing Cajal-Retzius cells in polymicrogyria
Eriksson et al.
Brain 2001;124:1350-1361.
ABSTRACT | FULL TEXT  

Increased CNS levels of apolipoprotein D in schizophrenic and bipolar subjects: Implications for the pathophysiology of psychiatric disorders
Thomas et al.
Proc. Natl. Acad. Sci. USA 2001;98:4066-4071.
ABSTRACT | FULL TEXT  

Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse
Liu et al.
Proc. Natl. Acad. Sci. USA 2001;98:3477-3482.
ABSTRACT | FULL TEXT  

The Pathophysiology of Psychosis May Be Nonspecific
JWatch Psychiatry 2001;2001:1-1.
FULL TEXT  

Identification of Reelin-induced Sites of Tyrosyl Phosphorylation on Disabled 1
Keshvara et al.
J. Biol. Chem. 2001;276:16008-16014.
ABSTRACT | FULL TEXT