| 1 | Neurochem. Res. 2004 Dec 29: 2293-302 |
|---|---|
| PMID | 15672553 |
| Title | Altered myelination of the hippocampal formation in subjects with schizophrenia and bipolar disorder. |
| Abstract | Myelination of the frontal and temporal lobes occurs at a similar time period as symptom onset in schizophrenia. To assess this potential relationship, we compared myelination and oligodendrocyte numbers in the hippocampal formation of controls and matched subjects with schizophrenia and bipolar disorder. The levels and distribution of the myelin marker myelin basic protein (MBP) and the oligodendrocyte marker adenomatous polyposis coli (APC) were measured using immunocytochemistry. MBP immunoreactivity (IR) was increased in several hippocampal subregions of control females versus control males. Female subjects with schizophrenia and bipolar disorder exhibited decreased myelination in the hippocampal formation while male subjects with bipolar disorder showed increased MBP levels in the superior medullary lamina. In contrast, the number of APC immunoreactive cells did not differ in any disorder or region. Our results demonstrate an interaction between gender, mental illness, and myelination, and may be related to cognitive deficits seen in schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Bipolar Disord 2005 Oct 7: 449-55 |
| PMID | 16176438 |
| Title | Reductions in cholesterol and synaptic markers in association cortex in mood disorders. |
| Abstract | Cholesterol forms an integral part of cell membranes and is a major component of myelin. Furthermore, cholesterol also plays a vital role in the development, function and stability of synapses. While low serum cholesterol has previously been associated with mood disorders, cholesterol levels have yet to be quantified within the brain in these disorders. The aim of this study was to quantify sterol levels in the brains of patients with major psychiatric disorders and further to relate these levels to markers of myelin and synapses. Samples of visual association cortex were obtained postmortem from subjects with bipolar disorder (BPD), major depressive disorder (MDD) and schizophrenia (SCZ) and from controls (all n = 15). Concentrations of brain cholesterol, its precursors lathosterol, desmosterol and lanosterol and its metabolite 24S-hydroxycholesterol were determined by gas-liquid chromatography. Immunoreactivity for myelin basic protein (MBP), synaptophysin and VAMP was quantified by enzyme-linked immunosorbent assay. Cholesterol levels were 13% lower in MDD (p = 0.018) and 10% lower in BPD (p = 0.052) compared with controls. Cholesterol precursor or metabolite concentrations did not differ between groups. Synaptophysin immunoreactivity was 20% lower in BPD (p = 0.025) and VAMP immunoreactivity 37% lower in MDD (p = 0.032) and 45% lower in BPD (p = 0.009). MBP immunoreactivity was not altered in any disorder. Our data suggest that lower brain cholesterol levels and a reduction in synapses may be features of mood disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neurobiol. Dis. 2006 Mar 21: 531-40 |
| PMID | 16213148 |
| Title | Myelin-associated mRNA and protein expression deficits in the anterior cingulate cortex and hippocampus in elderly schizophrenia patients. |
| Abstract | Microarray and other studies have reported oligodendrocyte and myelin-related (OMR) deficits in schizophrenia. Here, we employed a quantitative approach to determine the magnitude of OMR gene expression deficits and their brain-region specificity. In addition, we examined how expression levels among the studied OMR genes are interrelated. mRNA of MAG, CNP, SOX10, CLDN11, and PMP22, but not MBP and MOBP, was reduced in the hippocampus and anterior cingulate cortex but not in the putamen of patients with schizophrenia. Expression of the only protein examined (CNP) was decreased in the hippocampus but not in the putamen. Correlation and factor analyses revealed that mRNA levels for genes that did exhibit differential expression in schizophrenia (MAG, CNP, SOX10, CLDN11, and PMP2), as opposed to those that did not (MOBP and MBP), loaded on separate factors. Thus, OMR gene and protein expression deficits in schizophrenia are brain-region specific, and the affected components may share regulatory elements. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Hum. Mol. Genet. 2006 Mar 15: 743-9 |
| PMID | 16434481 |
| Title | DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling. |
| Abstract | Using bacterial artificial chromosome (BAC) array comparative genome hybridization (aCGH) at approximately 1.4 MBP resolution, we screened post-mortem brain DNA from bipolar disorder cases, schizophrenia cases and control individuals (n=35 each) for DNA copy-number aberrations. DNA copy number is a largely unexplored source of human genetic variation that may contribute risk for complex disease. We report aberrations at four loci which were seen in affected but not control individuals, and which were verified by quantitative real-time PCR. These aberrant loci contained the genes encoding EFNA5, GLUR7, CACNG2 and AKAP5; all brain-expressed proteins with known or postulated roles in neuronal function, and three of which (GLUR7, CACNG2 and AKAP5) are involved in glutamate signaling. A second cohort of psychiatric samples was also tested by quantitative PCR using the primer/probe sets for EFNA5, GLUR7, CACNG2 and AKAP5, and samples with aberrant copy number were found at three of the four loci (GLUR7, CACNG2 and AKAP5). Further scrutiny of these regions may reveal insights into the etiology and genetic risk factors for these complex psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | J. Neurol. Neurosurg. Psychiatr. 2006 Nov 77: 1284-7 |
| PMID | 17043297 |
| Title | Increased cerebrospinal fluid and serum levels of S100B in first-onset schizophrenia are not related to a degenerative release of glial fibrillar acidic protein, myelin basic protein and neurone-specific enolase from glia or neurones. |
| Abstract | To assess levels of glial fibrillar acidic protein (GFAP), myelin basic protein (MBP), neurone-specific enolase (NSE) and S100B in patients with first-onset schizophrenia. We investigated CSF and serum samples from 12 patients with first-onset schizophrenia and from 17 control subjects by ELISA (GFAP, MBP) or immunoluminometric sandwich assays (NSE, S100B). Patients with schizophrenia had significantly higher levels of S100B in CSF (p = 0.004; 2.73 (SD 0.80) v 1.92 (0.58) microg/l) and serum (p = 0.032; 0.09 (0.03) v 0.08 (0.02) microg/l) in comparison with those in the matched control group. No diagnosis-dependent differences of protein concentration were seen for GFAP, MBP and NSE. Our finding of increased levels of S100B in patients with schizophrenia without an indication for significant glial (GFAP, MBP) or neuronal (NSE) damage may be interpreted as indirect evidence for increased active secretion of S100B during acute psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Proc. Natl. Acad. Sci. U.S.A. 2006 May 103: 7482-7 |
| PMID | 16641098 |
| Title | Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. |
| Abstract | The quaking viable mouse mutation (qk(v)) is a deletion including the 5' regulatory region of the quaking gene (Qki), which causes body tremor and severe dysmyelination in mouse. The function of the human quaking gene, called quaking homolog KH domain RNA-binding (mouse) (QKI), is not well known. We have previously shown that QKI is a new candidate gene for schizophrenia. Here we show that human QKI mRNA levels can account for a high proportion (47%) of normal interindividual mRNA expression variation (and covariation) of six oligodendrocyte-related genes (PLP1, MAG, MBP, TF, SOX10, and CDKN1B) in 55 human brain autopsy samples from individuals without psychiatric diagnoses. In addition, the tightly coexpressed myelin-related genes (PLP1, MAG, and TF) have decreased mRNA levels in 55 schizophrenic patients, as compared with 55 control individuals, and most of this difference (68-96%) can be explained by variation in the relative mRNA levels of QKI-7kb, the same QKI splice variant previously shown to be down-regulated in patients with schizophrenia. Taken together, our results suggest that QKI levels may regulate oligodendrocyte differentiation and maturation in human brain, in a similar way as in mouse. Moreover, we hypothesize that previously observed decreased activity of myelin-related genes in schizophrenia might be caused by disturbed QKI splicing. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | J. Huazhong Univ. Sci. Technol. Med. Sci. 2006 -1 26: 228-30 |
| PMID | 16850754 |
| Title | Neuron-specific Enolase and myelin basic protein in cerebrospinal fluid of patients with first episode schizophrenia. |
| Abstract | In order to study whether patients with schizophrenia have cerebral injury, neuron-specific enolase (NSE) and myelin basic protein (MBP)in cerebrospinal fluid (CSF) of 33 patients with first episode schizophrenia and 9 from the control group were determined by double antibody sandwich enzyme immunoassay method. The results showed that there was significant difference in the NSE contents between the experimental group and control group (P<0.01). The NSE contents in CSF in the experimental group were positively correlated with MBP in schizophrenia patients (P< 0. 05). These findings suggested that patients with schizophrenia had cerebral injury. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Proc. Natl. Acad. Sci. U.S.A. 2006 May 103: 7482-7 |
| PMID | 16641098 |
| Title | Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. |
| Abstract | The quaking viable mouse mutation (qk(v)) is a deletion including the 5' regulatory region of the quaking gene (Qki), which causes body tremor and severe dysmyelination in mouse. The function of the human quaking gene, called quaking homolog KH domain RNA-binding (mouse) (QKI), is not well known. We have previously shown that QKI is a new candidate gene for schizophrenia. Here we show that human QKI mRNA levels can account for a high proportion (47%) of normal interindividual mRNA expression variation (and covariation) of six oligodendrocyte-related genes (PLP1, MAG, MBP, TF, SOX10, and CDKN1B) in 55 human brain autopsy samples from individuals without psychiatric diagnoses. In addition, the tightly coexpressed myelin-related genes (PLP1, MAG, and TF) have decreased mRNA levels in 55 schizophrenic patients, as compared with 55 control individuals, and most of this difference (68-96%) can be explained by variation in the relative mRNA levels of QKI-7kb, the same QKI splice variant previously shown to be down-regulated in patients with schizophrenia. Taken together, our results suggest that QKI levels may regulate oligodendrocyte differentiation and maturation in human brain, in a similar way as in mouse. Moreover, we hypothesize that previously observed decreased activity of myelin-related genes in schizophrenia might be caused by disturbed QKI splicing. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Trends Mol Med 2006 Mar 12: 107-12 |
| PMID | 16469540 |
| Title | Loss of autoimmune T cells correlates with brain diseases: possible implications for schizophrenia? |
| Abstract | T-cell-mediated autoimmunity participates in physiological defense, maintenance and repair of the adult brain. However, unless such autoimmune responses to insults are rigorously controlled, they might lead to an autoimmune disease or other immune-related defects, where destructive activity outweighs the beneficial effect. Here, we discuss these apparently contradictory effects of autoimmunity in schizophrenic patients, whose typical immune aberrations have prompted recent speculation about an autoimmune-related etiology. We found that, although schizophrenic patients have active immune systems, they often lack autoimmune clones specifically reactive to a major myelin protein, myelin basic protein (MBP). This, in conjunction with our discovery in rodents that T cells that recognize brain-resident proteins are needed for normal cognitive functioning, led us to propose an immune-based neurodevelopmental hypothesis, in which autoimmune-T-cell deficiency is suggested to cause onset or progression of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Trends Mol Med 2006 Mar 12: 107-12 |
| PMID | 16469540 |
| Title | Loss of autoimmune T cells correlates with brain diseases: possible implications for schizophrenia? |
| Abstract | T-cell-mediated autoimmunity participates in physiological defense, maintenance and repair of the adult brain. However, unless such autoimmune responses to insults are rigorously controlled, they might lead to an autoimmune disease or other immune-related defects, where destructive activity outweighs the beneficial effect. Here, we discuss these apparently contradictory effects of autoimmunity in schizophrenic patients, whose typical immune aberrations have prompted recent speculation about an autoimmune-related etiology. We found that, although schizophrenic patients have active immune systems, they often lack autoimmune clones specifically reactive to a major myelin protein, myelin basic protein (MBP). This, in conjunction with our discovery in rodents that T cells that recognize brain-resident proteins are needed for normal cognitive functioning, led us to propose an immune-based neurodevelopmental hypothesis, in which autoimmune-T-cell deficiency is suggested to cause onset or progression of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Mar 144B: 129-58 |
| PMID | 17266109 |
| Title | Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. |
| Abstract | Identifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, clock genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | J. Neurosci. Res. 2008 Aug 86: 2190-200 |
| PMID | 18438922 |
| Title | Maternal immune activation in mice delays myelination and axonal development in the hippocampus of the offspring. |
| Abstract | Epidemiological data suggest a relationship between maternal infection and a high incidence of schizophrenia in offspring. An animal model based on this hypothesis was made by injecting double-stranded RNA, polyinosinic-polycytidylic acid (poly-I:C), into early pregnant mice, and their offspring were examined for biochemical and histological abnormalities. Mouse brains were examined with special reference to oligodendrocytes, which have been implicated in several neurodevelopmental disorders. We detected a significant decrease of myelin basic protein (MBP) mRNA and protein at early postnatal periods in poly-I:C mice. MBP immunocytochemistry and electron microscopy revealed that the hippocampus of juvenile poly-I:C mice was less myelinated than in PBS mice, with no significant loss of oligodendrocytes. In addition, axonal diameters were significantly smaller in juvenile poly-I:C mice than in control mice. These abnormalities reverted to normal levels when the animals reached the adult stage. These findings suggest that retarded myelination and axonal abnormalities in early postnatal stages caused by maternal immune activation could be related to schizophrenia-related behaviors in adulthood. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Schizophr. Res. 2008 Jan 98: 118-28 |
| PMID | 18029146 |
| Title | Schizophrenia and sex associated differences in the expression of neuronal and oligodendrocyte-specific genes in individual thalamic nuclei. |
| Abstract | Considerable evidence based on the study of postmortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, the majority of the biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using Laser Capture Microdissection. The divisions studied were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | Schizophr. Res. 2008 Jan 98: 118-28 |
| PMID | 18029146 |
| Title | Schizophrenia and sex associated differences in the expression of neuronal and oligodendrocyte-specific genes in individual thalamic nuclei. |
| Abstract | Considerable evidence based on the study of postmortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, the majority of the biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using Laser Capture Microdissection. The divisions studied were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | Schizophr. Res. 2008 Dec 106: 182-91 |
| PMID | 18938062 |
| Title | Quetiapine alleviates the cuprizone-induced white matter pathology in the brain of C57BL/6 mouse. |
| Abstract | Recent human studies employing new magnetic resonance imaging techniques and micro-array analyses feature schizophrenia as a brain disease with alterations in white matter (WM), which is mainly composed of oligodendrocytes (OLs) and their processes wrapping around neuronal axons. To examine the putative role of OLs in the pathophysiology and treatment of schizophrenia, animal studies are essential. In the present study, C57BL/6 mice were given 0.2% cuprizone (CPZ) in their diet for five weeks during which they drank distilled water without or with quetiapine (QTP, 10 mg/kg). The mice fed with normal chow were used as controls. CPZ is a copper chelator and has been reported to induce consistent demyelination in the brain of C57BL/6 mouse by specifically damaging OLs. QTP is an atypical antipsychotic widely used in the treatment of schizophrenia and other psychotic disorders. In accordance with previous studies, CPZ-exposed mice showed pervasive myelin breakdown and demyelination. The amount of myelin basic protein (MBP) in the cerebral cortex was decreased by CPZ-exposure as shown in Western-blot analysis. In addition, the demyelinated sites were teemed with activated microglia and astrocytes but a few myelin forming OLs. Moreover, the activity of copper-zinc superoxide dismutase decreased in the cerebral cortex of CPZ-exposed mice. However, all of these pathological changes in WM were either prevented or alleviated in CPZ-exposed mice co-administered with QTP. These results suggest that the CPZ-exposed C57BL/6 mouse is a potential animal model to study possible roles of OLs in the pathogenesis and treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | J. Mol. Neurosci. 2009 May 38: 2-11 |
| PMID | 18836851 |
| Title | Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro. |
| Abstract | The discoidin domain receptor (DDR1) is highly expressed in oligodendrocytes during the neurodevelopmental myelination process and is genetically associated to schizophrenia. In this study, we aimed to further assess the involvement of DDR1 in both remyelination and oligodendrocyte differentiation. In the mouse model of demyelination-remyelination induced by oral administration of cuprizone, in situ hybridization showed an upregulation of the DDR1 gene in three different white matter areas (corpus callosum, dorsal fornix, and external capsule) during the remyelination period. Moreover, real time reverse transcriptase polymerase chain reaction showed that the increase in DDR1 messenger RNA (mRNA) was strongly correlated with the number of DDR1-positive cells in the corpus callosum (Spearman coefficient = 0.987, P = 0.013). Cells positive for DDR1 mRNA were also positive for oligodendrocyte markers (OLIG2, carnosine, and APC) but not for markers of oligodendrocyte precursors (NG2), myelin markers (CNPase), microglia (CD11b), or reactive glia (GFAP). Differentiation of a human oligodendroglial cell line, HOG16, was associated with an increase in mRNA expression of DDR1 and several myelin proteins (MBP and MOBP) but not other proteins (APC and CNPase). Here, we demonstrate that DDR1 is upregulated in vitro and in vivo when oligodendrocyte myelinating machinery is activated. Further studies are needed to identify the specific molecular pathway. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Schizophr. Res. 2009 Jul 112: 46-53 |
| PMID | 19487109 |
| Title | Abnormal expression of myelination genes and alterations in white matter fractional anisotropy following prenatal viral influenza infection at E16 in mice. |
| Abstract | Prenatal viral infection has been associated with the development of schizophrenia and autism. Our laboratory has previously shown that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) and late second trimester (E18) administration of influenza virus. We hypothesized that middle second trimester infection (E16) in mice may lead to a different pattern of brain gene expression and structural defects in the developing offspring. C57BL6 mice were infected on E16 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offspring of the infected mice were collected at P0, P14, P35, and P56, their brains removed and cerebella dissected and flash frozen. Microarray, DTI and MRI scanning, as well as qRT-PCR and SDS-PAGE and western blotting analyses were performed to detect differences in gene expression and brain atrophy. Expression of several genes associated with myelination, including MBP, Mag, and Plp1 were found to be altered, as were protein levels of MBP, Mag, and DM20. Brain imaging revealed significant atrophy in cerebellum at P14, reduced fractional anisotropy in white matter of the right internal capsule at P0, and increased fractional anisotropy in white matter in corpus callosum at P14 and right middle cerebellar peduncle at P56. We propose that maternal infection in mouse impacts myelination genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | Brain Res. 2009 Dec 1301: 126-34 |
| PMID | 19747901 |
| Title | Association between myelin basic protein expression and left entorhinal cortex pre-alpha cell layer disorganization in schizophrenia. |
| Abstract | There is evidence for migrational disturbances in the entorhinal cortex (ERC) in schizophrenia that supports a neurodevelopmental origin of the disorder. Since impaired myelin basic protein (MBP) gene expression during the migration phase could lead to abnormalities in final laminar position, we performed layer specific measurements of MBP expression in the ERC and hypothesised that migrational disturbances of pre-alpha-cell clusters relate to decreased MBP expression. Paraffin embedded sections of the left entorhinal cortex of 16 schizophrenia patients and 10 control subjects were stained for MBP using routine immunohistochemistry. On each section representative regions of interest were scanned to attain optimal quality images of the gray matter. Results were correlated to previous published disturbed dispersion of pre-alpha-cell clusters in adjacent brain sections. Mean MBP stain-intensity was significantly reduced in schizophrenia patients. Absolute MBP stain-intensity was significantly reduced in layers III and IV in patients. A significant correlation of MBP stain-intensity with the distance of the deep pole of the pre-alpha-cell cluster from the gray-white matter junction was observed in the ERC of schizophrenia patients. The present data provide evidence for reduced MBP expression in the ERC in schizophrenia, which implies deficits in axonal myelination and disturbed connectivity. MBP gene is expressed in oligodendrocytes and neuronal populations during embryonic development, which are important in establishing the structure of the cerebral cortex. Correlation between reduced MBP as a sign of down-regulated MBP gene expression and disorganization of pre-alpha-cell clusters supports a neurodevelopmental origin of pathological processes in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | Schizophr. Res. 2009 Apr 109: 159-66 |
| PMID | 19272755 |
| Title | Metabolic abnormalities in fronto-striatal-thalamic white matter tracts in schizophrenia. |
| Abstract | The anterior limb of the internal capsule (ALIC) is the major white matter tract providing reciprocal connections between the frontal cortex, striatum and thalamus. Mounting evidence suggests that this tract may be affected in schizophrenia, with brain imaging studies reporting reductions in white matter volume and density, changes in fractional anisotropy and reduced asymmetry. However, the molecular correlates of these deficits are currently unknown. The aim of this study was to identify alterations in protein and metabolite levels in the ALIC in schizophrenia. Samples were obtained post-mortem from individuals with schizophrenia (n=15) and non-psychiatric controls (n=13). Immunoreactivity for the myelin-associated protein myelin basic protein (MBP), and the axonal-associated proteins phosphorylated neurofilament and SNAP-25 was measured by enzyme-linked immunoadsorbent assay (ELISA). Metabolite concentrations were quantified by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. Levels of myelin- or axonal-associated proteins did not differ between groups. Overall differences in metabolite concentrations were observed between the two groups (MANOVA F=2.685, p=0.036), with post-hoc tests revealing lower lactate (19%) and alanine (24%) levels in the schizophrenia group relative to controls. Observed changes in lactate and alanine levels indicate metabolic abnormalities within the ALIC in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 20 | Int. J. Neuropsychopharmacol. 2009 Aug 12: 885-94 |
| PMID | 19154657 |
| Title | Association between golli-MBP and schizophrenia in the Jewish Ashkenazi population: are regulatory regions involved? |
| Abstract | Multiple studies have reported oligodendrocyte and myelin abnormalities, as well as dysregulation of their related genes, in brains of schizophrenia patients. One of these genes is the myelin-basic-protein (MBP) gene, which encodes two families of proteins: classic-MBPs and golli-MBPs. While the classic-MBPs are predominantly located in the myelin sheaths of the nervous system, the golli proteins are more widely expressed and are found in both the immune and the nervous systems. In the present study we performed a case-control association analysis of golli-MBP in two separate Jewish Ashkenazi cohorts (cohort I: 120 patients, 236 controls; cohort II: 379 patients, 380 controls). In addition we performed an expression analysis of golli-MBP mRNA in post-mortem dorsolateral prefrontal cortex samples of schizophrenia patients, and matched controls. In the first cohort we observed association between six (out of 26 genotyped) single nucleotide polymorphisms (SNPs) and the disease (p<0.05). Of these, three are from one linkage disequilibrium (LD) block which contains a CTCF binding region. Haplotype analysis revealed significant 'risk'/'protective' haplotypes (strongest p=0.005, each) for schizophrenia. The three SNPs (rs12458282, rs2008323, rs721286) were then genotyped in the second cohort. The combined results showed strong effects, both in the single marker and in haplotype analyses (strongest OR 1.77, p=0.0005; OR 1.61, p=0.00001, respectively). Sequencing the CTCF binding region revealed three SNPs in complete LD with the associated haplotypes, located in close proximity to the CTCF binding site. Expression analysis found no significant differences in golli-MBP mRNA levels. These findings suggest that golli-MBP is a possible susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 21 | Brain Res. 2010 Jun 1336: 22-9 |
| PMID | 20380825 |
| Title | Expression of the tyrosine kinase discoidin domain receptor 1 (DDR1) in human central nervous system myelin. |
| Abstract | During development of the mouse brain, the protein kinase discoidin domain receptor 1 (DDR1) is present prenatally in neurons of the proliferative areas, and postnatally, DDR1 expression is no longer detected in neurons, but a spatial-temporal expression pattern in oligodendrocytes that overlaps with the dynamics of the myelination process is detected. Notably, oligodendrocytic DDR1 expression is upregulated in mice during experimentally induced remyelination. Recently, we demonstrated that DDR1 expression is high in human brain and that there is an association between the gene and schizophrenia in a case-control study. However, data regarding expression of DDR1 in the human brain are scarce. Here, we describe the expression pattern of DDR1 in the human adult cerebral cortex. Using several immunohistological techniques and in situ hybridization, we identified DDR1 in the following: a) myelin, b) capillary endothelial cells in the gray as well as white matter, and c) in the soma of some oligodendrocytes and astrocytes in the white matter. The most important overall finding in this study was that DDR1 is present in myelin and is expressed by oligodendrocyte cells. We detected the presence of DDR1 mRNA and protein in myelin and observed that DDR1 co-localized with the classical myelin basic protein (MBP). Moreover, we found a strong positive correlation between expression levels of DDR1 and two myelin-associated genes, myelin-associated glycoprotein (MAG) and oligodendrocyte transcription factor 2 (OLIG2). These observations suggest that DDR1 could be an important constituent of myelin. Because defects in myelination are linked to several mental disorders such as schizophrenia, the function of DDR1 in the process of myelination warrants further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 22 | Front Behav Neurosci 2010 -1 4: 8 |
| PMID | 20305752 |
| Title | Behavioral and neurobiological changes in C57BL/6 mouse exposed to cuprizone: effects of antipsychotics. |
| Abstract | Recent human studies suggest a role for altered oligodendrocytes in the pathophysiology of schizophrenia. Our recent animal study has reported some schizophrenia-like behaviors in mice exposed to cuprizone (Xu et al., 2009), a copper chelator that has been shown to selectively damage the white matter. This study was to explore mechanisms underlying the behavioral changes in cuprizone-exposed mice and to examine effects of the antipsychotics haloperidol, clozapine and quetiapine on the changes in the mice. Mice given cuprizone for 14 days showed a deficit in the prepulse inhibition of acoustic startle response and higher dopamine in the prefrontal cortex (PFC), which changes were not seen in mice given cuprizone plus antipsychotics. Mice given cuprizone for 21 days showed lower spontaneous alternations in Y-maze, which was not seen in mice treated with cuprizone plus the antipsychotics. Mice given cuprizone for 28 days displayed less social interactions, which was not seen in mice given cuprizone plus clozapine/quetiapine, but was seen in mice given cuprizone plus haloperidol. Mice given cuprizone for 42 days showed myelin sheath loss and lower myelin basic protein in PFC, caudate putamen, and hippocampus. The white matter damage in PFC was attenuated in mice given cuprizone plus clozapine/haloperidol. But the white matter damage in caudate putamen and hippocampus was only attenuated by clozapine and quetiapine, not by haloperidol. These results help us to understand the behavioral changes and provide experimental evidence for the protective effects of antipsychotics on white matter damage in cuprizone-exposed mice. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 23 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Dec 156B: 808-16 |
| PMID | 21812102 |
| Title | Genomic architecture of aggression: rare copy number variants in intermittent explosive disorder. |
| Abstract | Copy number variants (CNVs) are known to be associated with complex neuropsychiatric disorders (e.g., schizophrenia and autism) but have not been explored in the isolated features of aggressive behaviors such as intermittent explosive disorder (IED). IED is characterized by recurrent episodes of aggression in which individuals act impulsively and grossly out of proportion from the involved stressors. Previous studies have identified genetic variants in the serotonergic pathway that play a role in susceptibility to this behavior, but additional contributors have not been identified. Therefore, to further delineate possible genetic influences, we investigated CNVs in individuals diagnosed with IED and/or personality disorder (PD). We carried out array comparative genomic hybridization on 113 samples of individuals with isolated features of IED (n?=?90) or PD (n?=?23). We detected a recurrent 1.35-MBP deletion on chromosome 1q21.1 in one IED subject and a novel ?350-kbp deletion on chromosome 16q22.3q23.1 in another IED subject. While five recent reports have suggested the involvement of an ?1.6-MBP 15q13.3 deletion in individuals with behavioral problems, particularly aggression, we report an absence of such events in our study of individuals specifically selected for aggression. We did, however, detect a smaller ?430-kbp 15q13.3 duplication containing CHRNA7 in one individual with PD. While these results suggest a possible role for rare CNVs in identifying genes underlying IED or PD, further studies on a large number of well-characterized individuals are necessary. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 24 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Dec 35: 1950-6 |
| PMID | 21839137 |
| Title | Olanzapine stimulates proliferation but inhibits differentiation in rat oligodendrocyte precursor cell cultures. |
| Abstract | In the developing brain, oligodendrocyte progenitor cells (OPCs) proliferate, migrate, and differentiate into mature oligodendrocytes (OLs) capable of myelinating axons. Recently, OPCs have been identified as an abundant and widespread population in the adult as well as in the developing animal. Current research indicates that these OPCs in the adult brain can proliferate and differentiate into myelinating OLs, albeit with different potentialities from those in developing animals. Multiple lines of evidence, from neuroimaging, postmortem, and genetic association studies, have implicated OL and myelin dysfunction in the pathogenesis of schizophrenia. If altered OL function is involved in pathogenesis, OPCs may thus respond to antipsychotic drugs during the recovery process. In the present study, we used primary OPC cultures from optic nerve of newborn Wistar rat pups to investigate the direct effects of haloperidol (HPD; a typical antipsychotic) and olanzapine (OLZ; an atypical antipsychotic) on the proliferation and differentiation of OPCs. Our results showed that 1) OLZ treatment significantly increased the number of viable OPCs when compared to HPD treatment at relatively high concentrations, 2) OLZ treatment suppressed the expression of myelin basic protein (MBP), and to a greater extent than HPD treatment, and 3) these pharmacological effects may be mediated via the ERK signaling pathway. Our findings suggest a glial mechanism for the antipsychotic action of OLZ, and a role for oligodendrocyte-lineage cells in the pathogenesis and treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 25 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Mar 156: 204-14 |
| PMID | 21302349 |
| Title | Inherited balanced translocation t(9;17)(q33.2;q25.3) concomitant with a 16p13.1 duplication in a patient with schizophrenia. |
| Abstract | We report two rare genetic aberrations in a schizophrenia patient that may act together to confer disease susceptibility. A previously unreported balanced t(9;17)(q33.2;q25.3) translocation was observed in two schizophrenia-affected members of a small family with diverse psychiatric disorders. The proband also carried a 1.5?MBP microduplication at 16p13.1 that could not be investigated in other family members. The duplication has been reported to predispose to schizophrenia, autism and mental retardation, with incomplete penetrance and variable expressivity. The t(9;17) (q33.2;q25.3) translocation breakpoint occurs within the open reading frames of KIAA1618 on 17q25.3, and TTLL11 (tyrosine tubulin ligase like 11) on 9q33.2, causing no change in the expression level of KIAA1618 but leading to loss of expression of one TTLL11 allele. TTLL11 belongs to a family of enzymes catalyzing polyglutamylation, an unusual neuron-specific post-translational modification of microtubule proteins, which modulates microtubule development and dynamics. The 16p13.1 duplication resulted in increased expression of NDE1, encoding a DISC1 protein partner mediating DISC1 functions in microtubule dynamics. We hypothesize that concomitant TTLL11-NDE1 deregulation may increase mutation load, among others, also on the DISC1 pathway, which could contribute to disease pathogenesis through multiple effects on neuronal development, synaptic plasticity, and neurotransmission. Our data illustrate the difficulties in interpreting the contribution of multiple potentially pathogenic changes likely to emerge in future next-generation sequencing studies, where access to extended families will be increasingly important. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 26 | PLoS ONE 2012 -1 7: e38211 |
| PMID | 22675524 |
| Title | Reduced myelin basic protein and actin-related gene expression in visual cortex in schizophrenia. |
| Abstract | Most brain gene expression studies of schizophrenia have been conducted in the frontal cortex or hippocampus. The extent to which alterations occur in other cortical regions is not well established. We investigated primary visual cortex (Brodmann area 17) from the Stanley Neuropathology Consortium collection of tissue from 60 subjects with schizophrenia, bipolar disorder, major depression, or controls. We first carried out a preliminary array screen of pooled RNA, and then used RT-PCR to quantify five mRNAs which the array identified as differentially expressed in schizophrenia (myelin basic protein [MBP], myelin-oligodendrocyte glycoprotein [MOG], ?-actin [ACTB], thymosin ?-10 [TB10], and superior cervical ganglion-10 [SCG10]). Reduced mRNA levels were confirmed by RT-PCR for MBP, ACTB and TB10. The MBP reduction was limited to transcripts containing exon 2. ACTB and TB10 mRNAs were also decreased in bipolar disorder. None of the transcripts were altered in subjects with major depression. Reduced MBP mRNA in schizophrenia replicates findings in other brain regions and is consistent with oligodendrocyte involvement in the disorder. The decreases in expression of ACTB, and the actin-binding protein gene TB10, suggest changes in cytoskeletal organisation. The findings confirm that the primary visual cortex shows molecular alterations in schizophrenia and extend the evidence for a widespread, rather than focal, cortical pathophysiology. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 27 | Mol. Psychiatry 2012 Sep 17: 887-905 |
| PMID | 22584867 |
| Title | Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. |
| Abstract | We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 28 | Brain Res. 2012 Aug 1469: 136-43 |
| PMID | 22750584 |
| Title | Myelination deficit in a phencyclidine-induced neurodevelopmental model of schizophrenia. |
| Abstract | Increasing evidence supports an important role of oligodendrocytes and myelination in the pathogenesis of schizophrenia. Oligodendrocytes are the myelin-producing cells in the central nervous system. To test the myelination dysfunction hypothesis of schizophrenia, possible myelination dysfunction was evaluated in a phencyclidine (PCP)-induced neurodevelopmental model of schizophrenia. On postnatal day (PND) 2, rat pups were treated with a total 14 subcutaneous daily injections of PCP (10mg/kg) or saline. PCP-injected rats showed schizophrenia-like behaviors including hyper-locomotor activity on PND 30 and prepulse inhibition deficit on PND 31. Cerebral myelination was measured by the expression of myelin basic protein (MBP), and cerebral mature oligodendrocytes were measured by the expression of glutathione S-transferase (GST)-? in rats. The results indicate that the expressions of MBP on PND 16, 22 and 32 and GST-? on PND 22 decreased in the frontal cortex of PCP-injected rats. Our results suggest that there was myelination impairment in the phencyclidine-induced schizophrenia animal model, and indicate that myelination may play an important role in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 29 | PLoS ONE 2012 -1 7: e38828 |
| PMID | 22723893 |
| Title | Segment-wise genome-wide association analysis identifies a candidate region associated with schizophrenia in three independent samples. |
| Abstract | Recent studies suggest that variation in complex disorders (e.g., schizophrenia) is explained by a large number of genetic variants with small effect size (Odds Ratio ? 1.05-1.1). The statistical power to detect these genetic variants in Genome Wide Association (GWA) studies with large numbers of cases and controls (v 15,000) is still low. As it will be difficult to further increase sample size, we decided to explore an alternative method for analyzing GWA data in a study of schizophrenia, dramatically reducing the number of statistical tests. The underlying hypothesis was that at least some of the genetic variants related to a common outcome are collocated in segments of chromosomes at a wider scale than single genes. Our approach was therefore to study the association between relatively large segments of DNA and disease status. An association test was performed for each SNP and the number of nominally significant tests in a segment was counted. We then performed a permutation-based binomial test to determine whether this region contained significantly more nominally significant SNPs than expected under the null hypothesis of no association, taking linkage into account. Genome Wide Association data of three independent schizophrenia case/control cohorts with European ancestry (Dutch, German, and US) using segments of DNA with variable length (2 to 32 MBP) was analyzed. Using this approach we identified a region at chromosome 5q23.3-q31.3 (128-160 MBP) that was significantly enriched with nominally associated SNPs in three independent case-control samples. We conclude that considering relatively wide segments of chromosomes may reveal reliable relationships between the genome and schizophrenia, suggesting novel methodological possibilities as well as raising theoretical questions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 30 | Proteomics 2013 Dec 13: 3548-53 |
| PMID | 24167090 |
| Title | The human oligodendrocyte proteome. |
| Abstract | Myelination of the CNS is performed by oligodendrocytes (OLs), which have been implicated in brain disorders, such as multiple sclerosis and schizophrenia. We have used the human oligodendroglial cell line MO3.13 to establish an OL reference proteome database. Proteins were prefractionationated by SDS-PAGE and after in-gel digestion subjected to nanoflow LC-MS analysis. Approximately 11?600 unique peptides were identified and, after stringent filtering, resulted in 2290 proteins representing nine distinct biological processes and various molecular classes and functions. OL-specific proteins, such as myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), as well as other proteins involved in multiple sclerosis and schizophrenia were also identified and are discussed. Proteins of this dataset have also been classified according to their chromosomal origin for providing useful data to the Chromosome-centric Human Proteome Project (C-HPP). Given the importance of OLs in the etiology of demyelinating and oligodendrogial disorders, the MO3.13 proteome database is a valuable data resource. The MS proteomics data have been deposited to the ProteomeXchange with identifier PXD000263 (http://proteomecentral.proteomexchange.org/dataset/PXD000263). |
| SCZ Keywords | schizophrenia, schizophrenic |
| 31 | J Psychiatr Res 2013 Aug 47: 1069-79 |
| PMID | 23615187 |
| Title | Increased nuclear Olig1-expression in the pregenual anterior cingulate white matter of patients with major depression: a regenerative attempt to compensate oligodendrocyte loss? |
| Abstract | Structural and functional oligodendrocyte deficits as well as impaired myelin integrity have been described in affective disorders and schizophrenia, and may disturb the connectivity between disease-relevant brain regions. Olig1, an oligodendroglial transcription factor, might be important in this context, but has not been systematically studied so far. Nissl- and Olig1-stained oligodendrocytes were quantified in the pregenual anterior cingulate (pACC)/dorsolateral prefrontal cortex (DLPFC), and adjacent white matter of patients with major depressive disorder (MDD, n = 9), bipolar disorder (BD, n = 8), schizophrenia (SZ, n = 13), and matched controls (n = 16). Potential downstream effects of increased Olig1-expression were analyzed. Antidepressant drug effects on Olig1-expression were further explored in OLN-93 oligodendrocyte cultures. Nissl-stainings of both white matter regions showed a 19-27% reduction of total oligodendrocyte densities in MDD and BD, but not in SZ. In contrast, nuclear Olig1-immunoreactivity was elevated in MDD in the pACC-adjacent white matter (left: p = 0.008; right: p = 0.018); this effect tended to increase with antidepressant dosage (r = 0.631, p = 0.069). This reactive increase of Olig1 was confirmed by partly dose-dependent effects of imipramine and amitriptyline in oligodendrocyte cultures. Correspondingly, MBP expression in the pACC-adjacent white matter tended to increase with antidepressant dosage (r = 0.637, p = 0.065). Other tested brain regions showed no diagnosis-dependent differences regarding Olig1-immunoreactivity. Since nuclear Olig1-expression marks oligodendrocyte precursor cells, its increased expression along with reduced total oligodendrocyte densities (Nissl-stained) in the pACC-adjacent white matter of MDD patients might indicate a (putatively medication-boosted) regenerative attempt to compensate oligodendrocyte loss. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 32 | Brain Behav. Immun. 2014 Jan 35: 64-9 |
| PMID | 24095895 |
| Title | In vitro-induced cell-mediated immune deviation to encephalitogenic antigens. |
| Abstract | The injection of antigens into the Anterior Chamber (AC) of the eye induces Anterior Chamber Associated Immune Deviation (ACAID), which is a potent form of immune deviation that is largely attributed to the effect of TGF?2 in the aqueous humor on ocular antigen-presenting cells (APCs). ACAID antigen presentation via APCs and B cells leads to the generation of antigen-specific T regulatory cells. The encephalitogenic antigens Myelin oligodendrocyte glycoprotein (MOG) and Myelin basic protein (MBP) have an obvious clinical relevance. We hypothesized that the intravenous injection of in vitro-generated ACAID APCs or in vitro-generated ACAID B cells specific to the encephalitogenic antigens MOG35-55/MBP induces specific peripheral tolerance in recipient BALB/c mice. We examined the suppression of MOG35-55-specific/MBP-specific inflammatory responses using delayed-type hypersensitivity (DTH) assays and Local Adoptive Transfer (LAT) assays. Results indicated that MOG35-55-specific/MBP-specific tolerance was generated after the intravenous injections of MOG35-55-specific/MBP-specific ACAID APCs, MOG35-55-specific/MBP-specific ACAID B cells, and MOG35-55-specific/MBP-specific ACAID T regulatory cells. The specific immune deviation was in vitro-induced, cell-mediated, and specific to the encephalitogenic antigens MOG35-55/MBP. This in vitro-mediated approach for the generation of MOG35-55/MBP-specific tolerance opens up avenues for the application of ACAID as a tool for the therapy of Multiple Sclerosis, schizophrenia, and other diseases. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 33 | J Clin Psychiatry 2014 Aug 75: e794-801 |
| PMID | 25191916 |
| Title | Combining serum protein concentrations to diagnose schizophrenia: a preliminary exploration. |
| Abstract | It is difficult for clinicians to diagnose schizophrenia solely based on interviews. We explored the diagnostic efficiency and predictive capability of serum biomarkers for schizophrenia. Levels of ? nerve growth factor (?-NGF), brain-derived neurotrophic factor (BDNF), interleukin 6 (IL-6), tumor necrosis factor ? (TNF-?), interferon ? (IFN-?), calcium binding protein S100?, myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) were measured in the sera of 278 schizophrenia patients, 240 depression and bipolar disorder patients, and 260 healthy controls. DSM-IV-TR criteria were used as the diagnostic criteria for schizophrenia and depressive and bipolar disorders. The diagnostic efficiency was high in patients with schizophrenia compared with the healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain the diagnostic efficiency of the 8 proteins. Data were collected between July 2010 and December 2012. One-way analysis of variance significantly demonstrated lower serum BDNF, MBP, and GFAP levels (F = 16.504, P < .001; F = 207.209, P < .001; F = 33.668, P < .001, respectively) but higher serum IL-6 and S100? concentrations (F = 15.250, P < .001; F = 12.751, P < .001, respectively) among patients with schizophrenia. ROC analysis of the discriminant scores of the serum ?-NGF, BDNF, IL-6, S100?, MBP, and GFAP levels resulted in significant discrimination between the schizophrenia and control groups (AUC = 0.922) and the depressive/bipolar disorder and control groups (AUC = 0.762). Serum levels of 6 proteins (but not TNF-? and IFN-?) contribute most to the diagnosis of schizophrenia. These proteins may prove to be useful adjuncts for the clinical assessment of this disease. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 34 | Transl Psychiatry 2014 -1 4: e348 |
| PMID | 24448210 |
| Title | Novel implications of Lingo-1 and its signaling partners in schizophrenia. |
| Abstract | Myelination and neurite outgrowth both occur during brain development, and their disturbance has been previously been implicated in the pathophysiology of schizophrenia. Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) is a potent negative regulator of axonal myelination and neurite extension. As co-factors of Lingo-1 signaling (Nogo receptor (NgR), With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1)) have been implicated in the genetics of schizophrenia, we explored for the first time the role of Lingo-1 signaling pathways in this disorder. Lingo-1 protein, together with its co-receptor and co-factor proteins NgR, tumor necrosis factor (TNF) receptor orphan Y (TROY), p75, WNK1 and Myt1, have never been explored in the pathogenesis of schizophrenia. We examined protein levels of Lingo-1, NgR, TROY, p75, WNK1, Myt1 and myelin basic protein (MBP) (as a marker of myelination) within the post-mortem dorsolateral prefrontal cortex (DLPFC) (37 schizophrenia patients versus 37 matched controls) and hippocampus (Cornu Ammonis, CA1 and CA3) (20 schizophrenia patients versus 20 matched controls from the same cohort). Both of these brain regions are highly disrupted in the schizophrenia pathophysiology. There were significant increases in Lingo-1 (P<0.001) and Myt1 (P=0.023) and a reduction in NgR (P<0.001) in the DLPFC in schizophrenia subjects compared with controls. There were also increases in both TROY (P=0.001) and WNK1 (P=0.011) in the CA1 of schizophrenia subjects and, in contrast to the DLPFC, there was an increase in NgR (P=0.006) in the CA3 of schizophrenia subjects compared with controls. No significant difference was reported for MBP levels (P>0.05) between the schizophrenia and control groups in the three tested regions. This is the first time that a study has shown altered Lingo-1 signaling in the schizophrenia brain. Our novel findings may present a direct application for the use of a Lingo-1 antagonist to complement current and future schizophrenia therapies. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 35 | Eur Arch Psychiatry Clin Neurosci 2014 Mar 264: 121-9 |
| PMID | 23728937 |
| Title | Differential effects of antipsychotics on the development of rat oligodendrocyte precursor cells exposed to cuprizone. |
| Abstract | Cuprizone (CPZ) is a copper-chelating agent and has been shown to induce white matter damage in mice and rats. The compromised white matter and oligodendrocytes (OLs) respond to some antipsychotics in vivo. However, little is known about the effects of antipsychotics on cultured OLs in the presence of CPZ. The aim of this study was to examine effects of some antipsychotics on developing OLs in the presence of CPZ. Oligodendrocyte progenitor cells (OPCs) were prepared from rat embryos; OLs at different developing stages were labeled with specific antibodies; levels of CNP and MBP proteins in mature OLs were assessed by Western-blot analysis; malondialdehyde (MDA) levels and activity of catalase were evaluated as well for an assessment of oxidative stress and antioxidative status. In immunofluorescent staining, CPZ was shown to inhibit the differentiation of cultured OPCs into O4-positive cells, reduce the maturation of O4-positive cells into CNP- and MBP-positive cells, and decrease levels of CNP and MBP in mature OLs. These inhibitory effects of CPZ were ameliorated by clozapine and quetiapine (QUE), but not by haloperidol and olanzapine. Further experiments were performed to explore the mechanism of the protective effects of QUE. QUE attenuated the decreases in CNP and MBP in CPZ-treated OLs, and blocked the CPZ-induced increase in MDA and decrease in catalase activity in cultured OLs. These results are relevant to the pathophysiology and treatment of schizophrenia considering the aberrant white matter development and evidence suggesting the derangement of the oxidant and antioxidant defense system in some of the patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 36 | Transl Psychiatry 2014 -1 4: e391 |
| PMID | 24844177 |
| Title | Genetic risk prediction and neurobiological understanding of alcoholism. |
| Abstract | We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) was used to generate a genetic risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) were used to generate a Genetic Risk Prediction Score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol-dependent individuals from controls in an independent German test cohort. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 37 | PLoS ONE 2014 -1 9: e88506 |
| PMID | 24516667 |
| Title | DISC1 (disrupted-in-schizophrenia-1) regulates differentiation of oligodendrocytes. |
| Abstract | Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a translocation, t(1;11) (q42.1;q14.3), that segregates with major psychiatric disorders, including schizophrenia, recurrent major depression and bipolar affective disorder, in a Scottish family. Here we report that mammalian DISC1 endogenously expressed in oligodendroglial lineage cells negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 expression was detected in oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA was expressed in primary cultured rat cortical oligodendrocyte precursor cells and decreased when oligodendrocyte precursor cells were induced to differentiate by PDGF deprivation. Immunocytochemical analysis showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. We show that expression of the myelin related markers, CNPase and MBP, as well as the number of cells with a matured oligodendrocyte morphology, were decreased following full length DISC1 overexpression. Conversely, both expression of CNPase and the number of oligodendrocytes with a mature morphology were increased following knockdown of endogenous DISC1 by RNA interference. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin related proteins and the number of mature oligodendrocytes, potentially acting via a dominant negative mechanism. We also identified involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of oligodendrocyte differentiation, both well-known transcription factors involved in the regulation of myelin genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 38 | Mol. Psychiatry 2015 Nov 20: 1266-85 |
| PMID | 26283638 |
| Title | Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach. |
| Abstract | Worldwide, one person dies every 40 seconds by suicide, a potentially preventable tragedy. A limiting step in our ability to intervene is the lack of objective, reliable predictors. We have previously provided proof of principle for the use of blood gene expression biomarkers to predict future hospitalizations due to suicidality, in male bipolar disorder participants. We now generalize the discovery, prioritization, validation, and testing of such markers across major psychiatric disorders (bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) in male participants, to understand commonalities and differences. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation and high suicidal ideation states (n=37 participants out of a cohort of 217 psychiatric participants followed longitudinally). We then used a convergent functional genomics (CFG) approach with existing prior evidence in the field to prioritize the candidate biomarkers identified in the discovery step. Next, we validated the top biomarkers from the prioritization step for relevance to suicidal behavior, in a demographically matched cohort of suicide completers from the coroner's office (n=26). The biomarkers for suicidal ideation only are enriched for genes involved in neuronal connectivity and schizophrenia, the biomarkers also validated for suicidal behavior are enriched for genes involved in neuronal activity and mood. The 76 biomarkers that survived Bonferroni correction after validation for suicidal behavior map to biological pathways involved in immune and inflammatory response, mTOR signaling and growth factor regulation. mTOR signaling is necessary for the effects of the rapid-acting antidepressant agent ketamine, providing a novel biological rationale for its possible use in treating acute suicidality. Similarly, MAOB, a target of antidepressant inhibitors, was one of the increased biomarkers for suicidality. We also identified other potential therapeutic targets or biomarkers for drugs known to mitigate suicidality, such as omega-3 fatty acids, lithium and clozapine. Overall, 14% of the top candidate biomarkers also had evidence for involvement in psychological stress response, and 19% for involvement in programmed cell death/cellular suicide (apoptosis). It may be that in the face of adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and organismal level. Finally, we tested the top increased and decreased biomarkers from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C), prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely independent test cohort of psychiatric participants for prediction of suicidal ideation (n=108), and in a future follow-up cohort of psychiatric participants (n=157) for prediction of psychiatric hospitalizations due to suicidality. The best individual biomarker across psychiatric diagnoses for predicting suicidal ideation was SLC4A4, with a receiver operating characteristic (ROC) area under the curve (AUC) of 72%. For bipolar disorder in particular, SLC4A4 predicted suicidal ideation with an AUC of 93%, and future hospitalizations with an AUC of 70%. SLC4A4 is involved in brain extracellular space pH regulation. Brain pH has been implicated in the pathophysiology of acute panic attacks. We also describe two new clinical information apps, one for affective state (simplified affective state scale, SASS) and one for suicide risk factors (Convergent Functional Information for Suicide, CFI-S), and how well they predict suicidal ideation across psychiatric diagnoses (AUC of 85% for SASS, AUC of 89% for CFI-S). We hypothesized a priori, based on our previous work, that the integration of the top biomarkers and the clinical information into a universal predictive measure (UP-Suicide) would show broad-spectrum predictive ability across psychiatric diagnoses. Indeed, the UP-Suicide was able to predict suicidal ideation across psychiatric diagnoses with an AUC of 92%. For bipolar disorder, it predicted suicidal ideation with an AUC of 98%, and future hospitalizations with an AUC of 94%. Of note, both types of tests we developed (blood biomarkers and clinical information apps) do not require asking the individual assessed if they have thoughts of suicide, as individuals who are truly suicidal often do not share that information with clinicians. We propose that the widespread use of such risk prediction tests as part of routine or targeted healthcare assessments will lead to early disease interception followed by preventive lifestyle modifications and proactive treatment. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 39 | Mol. Neurobiol. 2015 Oct -1: -1 |
| PMID | 26491028 |
| Title | Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naïve First Episode Psychosis. |
| Abstract | In schizophrenia, genetic and environmental factors affect neurodevelopment and neuroprogressive trajectory. Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression. However, it remains unclear whether circulating levels of cytokines and expression of these genes are associated, and how antipsychotic treatments impact this association. Relationships between messenger RNA (mRNA) expression of 11 schizophrenia-related genes and circulating levels of cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-?) were analyzed in 174 antipsychotic naïve first episode psychosis (FEP) and in 77 healthy controls. A subgroup of 72 patients was reassessed after treatment with risperidone. FEP patients were divided into those with and without depression. FEP patients with depression showed increased COMT expression and decreased NDEL1 expression. Increased IL-6 was associated with lowered AKT1 and DROSHA expression, while increased IL-10 was associated with increased NDEL1, DISC1, and MBP expression. IL-6 levels significantly increased the risperidone-induced expression of AKT1, DICER1, DROSHA, and COMT mRNA. The differential mRNA gene expression in FEP is largely associated with increased cytokine levels. While increased IL-6 may downregulate AKT-mediated cellular functions and dysregulate genes involved in microRNA (miRNA) machinery, increased IL-10 has neuroprotective properties. Increased IL-6 levels may prime the expression of genes (AKT1, DICER1, DROSHA, and COMT) in response to risperidone, suggesting that cytokine?×?treatment?×?gene interactions may improve cell function profiles. FEP patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 40 | Neurosci Bull 2015 Feb 31: 43-52 |
| PMID | 24831436 |
| Title | The schizophrenia/bipolar disorder candidate gene GNB1L is regulated in human temporal cortex by a cis-acting element located within the 3'-region. |
| Abstract | 22q11.2 deletion syndrome (DS) is a complex developmental disorder with a high incidence of psychiatric illnesses, including schizophrenia and mood disorders. Recent studies have identified Guanine Nucleotide Binding Protein (G protein) Beta Polypeptide 1-Like (GNB1L), located within the 1.5 MBP 22q11.2 DS critical region, as a candidate liability gene for schizophrenia and bipolar disorder. In this study, we used mRNA expression measurements in Han Chinese postmortem temporal cortex and linkage disequilibrium (LD) analysis to show that GNB1L is regulated by a cis-acting genetic variant within the 3'-region of the gene. Significantly, this variant is located within an LD block that contains all of the common SNPs previously shown to associate with schizophrenia and bipolar disorder in Han Chinese and Caucasian populations. Contrary to our expectations, re-analysis of previously published case-control study data in light of our mRNA expression results implies that the GNB1L high-expression allele is the risk allele for schizophrenia and bipolar disorder in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 41 | Int. J. Neuropsychopharmacol. 2015 Jan 18: -1 |
| PMID | 25539505 |
| Title | Targeted multiplexed selected reaction monitoring analysis evaluates protein expression changes of molecular risk factors for major psychiatric disorders. |
| Abstract | Extensive research efforts have generated genomic, transcriptomic, proteomic, and functional data hoping to elucidate psychiatric pathophysiology. Selected reaction monitoring, a recently developed targeted proteomic mass spectrometric approach, has made it possible to evaluate previous findings and hypotheses with high sensitivity, reproducibility, and quantitative accuracy. Here, we have developed a labelled multiplexed selected reaction monitoring assay, comprising 56 proteins previously implicated in the aetiology of major psychiatric disorders, including cell type markers or targets and effectors of known psychopharmacological interventions. We analyzed postmortem anterior prefrontal cortex (Brodmann area 10) tissue of patients diagnosed with schizophrenia (n=22), bipolar disorder (n=23), and major depressive disorder with (n=11) and without (n=11) psychotic features compared with healthy controls (n=22). Results agreed with several previous studies, with the finding of alterations of Wnt-signalling and glutamate receptor abundance predominately in bipolar disorder and abnormalities in energy metabolism across the neuropsychiatric disease spectrum. Calcium signalling was predominantly affected in schizophrenia and affective psychosis. Interestingly, we were able to show a decrease of all 4 tested oligodendrocyte specific proteins (MOG, MBP, MYPR, CNPase) in bipolar disorder and to a lesser extent in schizophrenia and affective psychosis. Finally, we provide new evidence linking ankyrin 3 specifically to affective psychosis and the 22q11.2 deletion syndrome-associated protein septin 5 to schizophrenia. Our study highlights the potential of selected reaction monitoring to evaluate the protein abundance levels of candidate markers of neuropsychiatric spectrum disorders, providing a high throughput multiplex platform for validation of putative disease markers and drug targets. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 42 | Eur Neuropsychopharmacol 2015 Dec 25: 2416-25 |
| PMID | 26476704 |
| Title | Increased expression of NDEL1 and MBP genes in the peripheral blood of antipsychotic-naïve patients with first-episode psychosis. |
| Abstract | schizophrenia is a multifactorial neurodevelopmental disorder with high heritability. First-episode psychosis (FEP) is a critical period for determining the disease prognosis and is especially helpful for identifying potential biomarkers associated with the onset and progression of the disorder. We investigated the mRNA expression of 12 schizophrenia-related genes in the blood of antipsychotic-naïve FEP patients (N=73) and healthy controls (N=73). To evaluate the influences of antipsychotic treatment and progression of the disorder, we compared the gene expression within patients before and after two months of treatment with risperidone (N=64). We observed a significantly increased myelin basic protein (MBP) and nuclear distribution protein nudE-like 1 (NDEL1) mRNA levels in FEP patients compared with controls. Comparing FEP before and after risperidone treatment, no significant differences were identified; however; a trend of relatively low NDEL1 expression was observed after risperidone treatment. Animals chronically treated with saline or risperidone exhibited no significant change in Ndel1 expression levels in the blood or the prefrontal cortex (PFC), suggesting that the trend of low NDEL1 expression observed in FEP patients after treatment is likely due to factors other than risperidone treatment (i.e., disease progression). In addition to the recognized association with schizophrenia, MBP and NDEL1 gene products also play an essential role in the functions that are deregulated in schizophrenia, such as neurodevelopment. Our data strengthen the importance of these biological processes in psychotic disorders, indicating that these changes can be detected peripherally and potentially represent putative novel blood biomarkers of susceptibility and disorder progression. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 43 | World J. Biol. Psychiatry 2015 Jun -1: 1-6 |
| PMID | 26089098 |
| Title | Gene expression analysis in blood of ultra-high risk subjects compared to first-episode of psychosis patients and controls. |
| Abstract | This study aimed to investigate peripheral blood gene expression in ultra-high-risk subjects (UHR) compared to first-episode psychosis individuals (FEP) and healthy controls (HC). We enrolled 22 UHR, 66 FEP and 67 HC and investigated the expression of 12 genes using Taqman assays. We used the Univariate General Linear Model, as well as Bonferroni correction for multiple comparisons. We found that UFD1L (ubiquitin fusion degradation 1 like (yeast)) gene was upregulated in UHR group compared to HC and FEP (P = 3.44 × 10(-6) ; P = 9.41 × 10(-6)). MBP (myelin basic protein) was downregulated in UHR compared to FEP (P = 6.07 × 10(-6)). DISC1 (disrupted in schizophrenia 1) was also upregulated in UHR compared to FEP but lost statistical significance when corrected for age. These genes are directly related to neurodevelopmental processes and have been associated to schizophrenia. Recent findings described that DISC1 overexpression can disrupt MBP expression, thus, we think that these alterations in UHR individuals could be associated with a common process. UFD1L showed a different pattern of expression only for UHR group, suggesting that they can be under an acute endoplasmatic reticulum stress, demanding elevated levels of Ufd1. Further studies can improve knowledge on disease progression and putative targets to preventive strategies. |
| SCZ Keywords | schizophrenia, schizophrenic |