Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia

Hof, Patrick R.; Haroutunian, Vahram; Friedrich, Victor L.; Byne, William; Buitron, Cristian; Perl, Daniel P.; Davis, Kenneth L.

doi:10.1016/s0006-3223(03)00237-3

Cited by 389 publications

(250 citation statements)

References 63 publications

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“…33,[72][73][74][75] Moreover, several studies have evidence for deficits in oligodendrocytes in the disorder. [76][77][78][79] These oligodendrocyte abnormalities may in turn contribute to the loss of coherence of axon tracts, and reduced connectivity, in schizophrenia. 80,81 Alterations in NRG1-ERBB4 and/or PTPRZ1 signaling may cause these oligodendrocyte abnormalities, in addition to potential neuronal effects.…”

Section: Discussionmentioning

confidence: 99%

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

et al. 2007

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Neuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase b/f (RPTPb), we postulated that simultaneous binding of MAGI proteins to RPTPb and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPb. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPb for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n = B1400). PTPRZ1, which codes for RPTPb, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P = 0.0003; gene-wide P = 0.0064; hypothesiswide P = 0.026). The data provide evidence for a role of PTPRZ1, and for RPTPb signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPb in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

et al. 2007

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“…[49][50][51][52] At the molecular level, transcriptional downregulation of oligodendrocyte-and myelin-related genes has been detected through microarray-based analyses in pre-frontal cortex samples from patients with schizophrenia. [53][54][55] It is of note that the myelination processes that occur during late-adolescence-to-early-adulthood (the time of peak incidence of schizophrenia onset) are concentrated in the frontal and temporal lobes; brain regions that are critical in the development of schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia

et al. 2007

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Evidence suggests that myelin alterations could predispose to schizophrenia. Reduced expression of several myelin genes has been observed in schizophrenia patients. Recently, we identified the discoidin domain receptor 1 (DDR1; located at human chromosome 6p21.3) as a myelin gene in the mouse model and in a human oligodendroglial cell line. In the present study we screened for single nucleotide polymorphisms (SNPs) in the DNA from 100 schizophrenia patients. We identified a novel mutation within exon 10 that produces the amino-acid substitution N502S in the a-d isoforms, and M475V in the e isoform. However the frequency of the mutation (2%) was similar in schizophrenia patients and in control subjects. In a casecontrol assessment with 389 schizophrenic patients and 615 controls, we identified one SNP (SNP9, rs1049623) associated with schizophrenia (odds ratio = 1.44, 95% confidence interval: 1.15-1.79, adjusted P = 0.0016). This association was confirmed in haplotype analysis; the SNPs 9-10-11 (rs1049623, rs2267641 and rs2239518) haplotype remaining significant even after adjustment for multiple testing (adjusted P = 0.0136). Of note was a strong gender dependence in the association, that is, statistical significance restricted to men (adjusted P-value = 0.0002). Regression analysis of DDR1 mRNA expression in peripheral blood lymphocytes from schizophrenia patients showed that the presence of the G allele significantly decreased the relative number of mRNA copies in a dose-dependent manner (P = 0.003). These data suggest that the risk haplotype tags a cis-acting variant involved in the transcription regulation system of the gene. In conclusion, we propose the DDR1 as a new susceptibility gene for schizophrenia.

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“…Furthermore, Uranova et al (2001) study, using electron microscopy, showed both qualitative and quantitative abnormalities in post-mortem brains of schizophrenics in the oligodentroglia in the prefrontal cortex and caudate nucleus, including a marked increase in the density of concentric lamellar bodies (indicating damage to myelinated fibers) in the caudate nucleus in post-mortem brains of patients diagnosed with schizophrenia, as well as decreased density of the oligodendrocytes in layer IV of the prefrontal cortex in schizophrenia (Uranova et al, 2004). In another study, Hof et al (2003) found decreased oligodendrocyte number and density in layer III of Brodmann area 9 and in gyral prefrontal white matter in schizophrenia.…”

Section: Introductionmentioning

confidence: 92%

A review of diffusion tensor imaging studies in schizophrenia

Kubicki

McCarley

Westin

et al. 2007

Journal of Psychiatric Research

682

523

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Both post-mortem and neuroimaging studies have contributed significantly to what we know about the brain and schizophrenia. MRI studies of volumetric reduction in several brain regions in schizophrenia have confirmed early speculations that the brain is disordered in schizophrenia. There is also a growing body of evidence suggesting that a disturbance in connectivity between different brain regions, rather than abnormalities within the separate regions themselves, are responsible for the clinical symptoms and cognitive dysfunctions observed in this disorder. Thus an interest in white matter fiber tracts, subserving anatomical connections between distant, as well as proximal, brain regions, is emerging. This interest coincides with the recent advent of diffusion tensor imaging (DTI), which makes it possible to evaluate the organization and coherence of white matter fiber tracts. This is an important advance as conventional MRI techniques are insensitive to fiber tract direction and organization, and have not consistently demonstrated white matter abnormalities. DTI may, therefore, provide important new information about neural circuitry, and it is increasingly being used in neuroimaging studies of psychopathological disorders. Of note, in the past five years 18 DTI studies in schizophrenia have been published, most describing white matter abnormalities. Questions still remain, however, regarding what we are measuring that is abnormal in this disease, and how measures obtained using one method correspond to those obtained using other methods? Below we review the basic principles involved in MR-DTI, followed by a review of the different methods used to evaluate diffusion. Finally, we review MR-DTI findings in schizophrenia.

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Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia

Cited by 389 publications

References 63 publications

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia

A review of diffusion tensor imaging studies in schizophrenia

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