Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

Genetic linkage and association have implicated neuregulin-1 (NRG-1) as a schizophrenia susceptibility gene. We measured mRNA expression levels of the three major isoforms of NRG-1 (ie type I, type II, and type III) in the postmortem dorsolateral prefrontal cortex (DLPFC) from matched patients and controls using real-time quantitative RT-PCR. Expression levels of three internal controls—GAPDH, cyclophilin, and β-actin—were unchanged in schizophrenia, and there were no changes in the absolute levels of the NRG-1 isoforms. However, type I expression normalized by GAPDH levels was significantly increased in schizophrenia DLPFC (by 23%) and positively correlated with antipsychotic medication dosage. Type II/type I and type II/type III ratios were significantly decreased (18 and 23% respectively). There was no effect on the NRG-1 mRNA levels of genotype at two SNPs previously associated with schizophrenia, suggesting that these alleles are not functionally responsible for abnormal NRG-1 expression patterns in patients. Subtle abnormalities in the expression patterns of NRG-1 mRNA isoforms in DLPFC may be associated with schizophrenia.

[1]  K. Kendler.  Seminars in Psychiatric Genetics , 1996 .

[2]  R. Gerlai,et al.  Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks , 2000, Behavioural Brain Research.

[3]  J. Coyle,et al.  Glutamatergic mechanisms in schizophrenia. , 2003, Annual review of pharmacology and toxicology.

[4]  N. Šestan,et al.  Neuregulin 1–erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Paul J. Harrison,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Genes for Schizophrenia? Recent Findings and Their Pathophysiological Implications , 2022 .

[6]  P. Goldman-Rakic,et al.  Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca's area 44 and area 9. , 2003, Archives of general psychiatry.

[7]  F. Benes,et al.  GABAergic Interneurons: Implications for Understanding Schizophrenia and Bipolar Disorder , 2001, Neuropsychopharmacology.

[8]  E. Torrey.  Surviving Schizophrenia: A Family Manual , 1983 .

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

[10]  J. Pierri,et al.  Lamina-specific deficits in parvalbumin-immunoreactive varicosities in the prefrontal cortex of subjects with schizophrenia: evidence for fewer projections from the thalamus. , 2001, The American journal of psychiatry.

[11]  G. Fischbach,et al.  Neuregulins Increase α7 Nicotinic Acetylcholine Receptors and Enhance Excitatory Synaptic Transmission in GABAergic Interneurons of the Hippocampus , 2001, The Journal of Neuroscience.

[12]  K. Murray,et al.  Neuregulin Signaling Regulates Neural Precursor Growth and the Generation of Oligodendrocytes In Vitro , 2001, The Journal of Neuroscience.

[13]  C. Birchmeier,et al.  Multiple essential functions of neuregulin in development , 1995, Nature.

[14]  G. Fischbach,et al.  Neuregulin Expression at Neuromuscular Synapses Is Modulated by Synaptic Activity and Neurotrophic Factors , 2002, The Journal of Neuroscience.

[15]  A. Sampson,et al.  Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia. , 2001, Archives of general psychiatry.

[16]  Daniel R. Weinberger,et al.  Prefrontal neurons and the genetics of schizophrenia , 2001, Biological Psychiatry.

[17]  F. Bloom,et al.  Psychopharmacology: The Fourth Generation of Progress , 1995 .

[18]  Michael Sasner,et al.  Neuregulin-β induces expression of an NMDA-receptor subunit , 1997, Nature.

[19]  P. Rakic,et al.  Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. , 1997, Development.

[20]  D. R. Clive,et al.  Neonatal Oligodendrocytes Contain and Secrete Neuregulins In Vitro , 1997, Journal of neurochemistry.

[21]  J. Kleinman,et al.  Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia , 2003, Molecular Psychiatry.

[22]  G. Fischbach,et al.  ARIA: a neuromuscular junction neuregulin. , 1997, Annual review of neuroscience.

[23]  M. Ozaki,et al.  Neuregulin-beta induces expression of an NMDA-receptor subunit. , 1997, Nature.

[24]  H. Yeh,et al.  Neuregulin Induces GABAA Receptor Subunit Expression and Neurite Outgrowth in Cerebellar Granule Cells , 1999, The Journal of Neuroscience.

[25]  G. Devries,et al.  Neuregulins in Glial Cells , 1998, Neurochemical Research.

[26]  D. Pitt,et al.  Neuregulin and erbB receptor expression in normal and diseased human white matter , 1999, Journal of Neuroimmunology.

[27]  G Kalsi,et al.  Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23. , 2001, American journal of human genetics.

[28]  P. Canoll,et al.  GGF/Neuregulin Is a Neuronal Signal That Promotes the Proliferation and Survival and Inhibits the Differentiation of Oligodendrocyte Progenitors , 1996, Neuron.

[29]  J. Ott,et al.  Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. , 1995, American journal of medical genetics.

[30]  Kari Stefansson,et al.  Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. , 2003, American journal of human genetics.

[31]  J. Gault,et al.  Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. , 2002, Archives of general psychiatry.

[32]  W. Honer,et al.  Linkage of familial schizophrenia to chromosome 13q32. , 1999, American journal of human genetics.

[33]  L. Role,et al.  A Cysteine-Rich Isoform of Neuregulin Controls the Level of Expression of Neuronal Nicotinic Receptor Channels during Synaptogenesis , 1998, Neuron.

[34]  S. Higashiyama,et al.  Regulation of Neuregulin Expression in the Injured Rat Brain and Cultured Astrocytes , 2001, The Journal of Neuroscience.

[35]  C. Birchmeier,et al.  Neuregulin, a factor with many functions in the life of a Schwann cell , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[36]  G. Fischbach,et al.  Neuregulin and ErbB receptor signaling pathways in the nervous system , 2001, Current Opinion in Neurobiology.

[37]  S. Carroll,et al.  Neuregulin–1 and ErbB4 Immunoreactivity Is Associated with Neuritic Plaques in Alzheimer Disease Brain and in a Transgenic Model of Alzheimer Disease , 2003, Journal of neuropathology and experimental neurology.

[38]  D. Talmage,et al.  Cysteine-Rich Domain Isoforms of the Neuregulin-1 Gene Are Required for Maintenance of Peripheral Synapses , 2000, Neuron.

[39]  L. Selemon,et al.  Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder , 2001, Biological Psychiatry.

[40]  D. Weinberger,et al.  Cell biology of the hippocampal formation in schizophrenia , 1999, Biological Psychiatry.

[41]  G. Fischbach,et al.  A role for the acetylcholine receptor-inducing protein ARIA in oligodendrocyte development. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[42]  H. Stefánsson,et al.  Neuregulin 1 and susceptibility to schizophrenia. , 2002, American journal of human genetics.

[43]  T. Matise,et al.  NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. , 1998, American journal of medical genetics.

[44]  T. Crow,et al.  A genome-wide search for schizophrenia susceptibility genes. , 1998, American journal of medical genetics.

[45]  W H Wong,et al.  Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[46]  R. Straub,et al.  Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes , 2002, Molecular Psychiatry.

[47]  J. Kleinman,et al.  The neuroanatomy and neurochemistry of schizophrenia. , 1998, The Psychiatric clinics of North America.

[48]  R. Straub,et al.  Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families. , 1996, The American journal of psychiatry.

[49]  C. Robert Cloninger,et al.  Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). , 2001, American journal of medical genetics.

[50]  Patrick R. Hof,et al.  Molecular and Cellular Evidence for an Oligodendrocyte Abnormality in Schizophrenia , 2002, Neurochemical Research.

[51]  E. Gershon,et al.  Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia , 2002, Molecular Psychiatry.

[52]  L. DeLisi,et al.  Genome-wide scan for linkage to schizophrenia in a Spanish-origin cohort from Costa Rica. , 2002, American journal of medical genetics.

[53]  C. Stefanis,et al.  Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21 , 1998, Nature Genetics.