Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia

Neuropathological and brain imaging studies suggest that schizophrenia may result from neurodevelopmental defects. Cytoarchitectural studies indicate cellular abnormalities suggestive of a disruption in neuronal connectivity in schizophrenia, particularly in the dorsolateral prefrontal cortex. Yet, the molecular mechanisms underlying these findings remain unclear. To identify molecular substrates associated with schizophrenia, DNA microarray analysis was used to assay gene expression levels in postmortem dorsolateral prefrontal cortex of schizophrenic and control patients. Genes determined to have altered expression levels in schizophrenics relative to controls are involved in a number of biological processes, including synaptic plasticity, neuronal development, neurotransmission, and signal transduction. Most notable was the differential expression of myelination-related genes suggesting a disruption in oligodendrocyte function in schizophrenia.

[1]  L. Goldstein,et al.  Kinesin Light Chains Are Essential for Axonal Transport in Drosophila , 1998, The Journal of cell biology.

[2]  K. Davis,et al.  Dopamine in schizophrenia: a review and reconceptualization. , 1991, The American journal of psychiatry.

[3]  J. Trojanowski,et al.  Recent advances in defining the neuropathology of schizophrenia , 1996, Acta Neuropathologica.

[4]  W. Bunney,et al.  Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia , 2000, Brain Research Reviews.

[5]  K. Davis,et al.  Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases. , 1998, Archives of general psychiatry.

[6]  D. Riethmacher,et al.  Severe neuropathies in mice with targeted mutations in the ErbB3 receptor , 1997, Nature.

[7]  D. Weinberger,et al.  Schizophrenia as a developmental disorder of the cerebral cortex , 1998, Current Opinion in Neurobiology.

[8]  J. Sangiovanni,et al.  Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[9]  Pat Levitt,et al.  Molecular Characterization of Schizophrenia Viewed by Microarray Analysis of Gene Expression in Prefrontal Cortex , 2000, Neuron.

[10]  S. Daviss,et al.  Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindin-immunoreactive neurons , 1995, Psychiatry Research.

[11]  P S Goldman-Rakic,et al.  Cytoarchitectonic definition of prefrontal areas in the normal human cortex: I. Remapping of areas 9 and 46 using quantitative criteria. , 1995, Cerebral cortex.

[12]  J. Tanaka,et al.  Localization and characterization of gelsolin in nervous tissues: gelsolin is specifically enriched in myelin-forming cells , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  Ben A. Barres,et al.  Axonal Control of Oligodendrocyte Development , 1999, The Journal of cell biology.

[14]  Paul J. Harrison.  The neuropathology of schizophrenia , 2008 .

[15]  N. Perrone-Bizzozero,et al.  Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  A. Minkowski,et al.  Regional Development of the Brain in Early Life , 1968 .

[17]  T M Hyde,et al.  Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. , 1992, Archives of neurology.

[18]  Peter E. Braun,et al.  Overexpression of 2′,3′-Cyclic Nucleotide 3′-Phosphodiesterase in Transgenic Mice Alters Oligodendrocyte Development and Produces Aberrant Myelination , 1996, Molecular and Cellular Neuroscience.

[19]  P. Goldman-Rakic,et al.  Increased volume and glial density in primate prefrontal cortex associated with chronic antipsychotic drug exposure , 1999, Biological Psychiatry.

[20]  K O Lim,et al.  Proton magnetic resonance spectroscopic imaging of cortical gray and white matter in schizophrenia. , 1998, Archives of general psychiatry.

[21]  J. Ehrhardt,et al.  Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. , 1994, Science.

[22]  P. Goldman-Rakic,et al.  Functional and anatomical aspects of prefrontal pathology in schizophrenia. , 1997, Schizophrenia bulletin.

[23]  B. Trapp.  Myelin‐Associated Glycoprotein Location and Potential Functions a , 1990, Annals of the New York Academy of Sciences.

[24]  M. Frank.  MAL, a proteolipid in glycosphingolipid enriched domains: functional implications in myelin and beyond , 2000, Progress in Neurobiology.

[25]  R. Lenox,et al.  Comparative distribution of myristoylated alanine‐rich C kinase substrate (MARCKS) and F1/GAP‐43 gene expression in the adult rat brain , 1997, The Journal of comparative neurology.

[26]  J. Kapfhammer,et al.  Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice , 1995, Cell.

[27]  J. R. Koehler,et al.  Modern Applied Statistics with S-Plus. , 1996 .

[28]  F. Benes,et al.  Emerging principles of altered neural circuitry in schizophrenia , 2000, Brain Research Reviews.

[29]  M. Schachner,et al.  Multiple functions of the myelin‐associated glycoprotein MAG (siglec‐4a) in formation and maintenance of myelin , 2000, Glia.

[30]  K. Nave,et al.  Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. , 1998, Science.

[31]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Bruce D. Trapp,et al.  Axonal pathology in myelin disorders , 1999, Journal of neurocytology.

[33]  F. Benes,et al.  Myelination of cortical-hippocampal relays during late adolescence. , 1989, Schizophrenia bulletin.

[34]  S. P. Fodor,et al.  High density synthetic oligonucleotide arrays , 1999, Nature Genetics.

[35]  Calvin L. Williams,et al.  Modern Applied Statistics with S-Plus , 1997 .

[36]  C. Li,et al.  Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[37]  P. Greengard,et al.  Beyond the Dopamine Receptor: Review the DARPP-32/Protein Phosphatase-1 Cascade , 1999 .

[38]  M. Owen.  Molecular genetic studies of schizophrenia , 2000, Brain Research Reviews.