ould you be able to assist me with reading the attached article and answering two questions? About a

ould you be able to assist me with reading the attached article and answering two questions? About a paragraph for an answer? 1) What are at least two pieces of evidence the article gives about how oligodendrocytes or myelin might be involved in schizophrenia? 2) What is at least one aspect of this area that needs further research?International Journal of Neuropsychopharmacology (2007), 10, 503511. Copyright f 2007 CINPdoi:10.1017/S146114570600722XOligodendrocyte pathophysiology : a newview of schizophreniaS P EC I A L S EC T I O NCINPDevorah Segal, Jessica R. Koschnick, Linda H. A. Slegers and Patrick R. HofDepartment of Neuroscience, Mount Sinai School of Medicine, New York, NY, USAAbstractA recent focus of schizophrenia research is disruption of white-matter integrity as a key facet of thiscomplex disorder. This was spurred, partly, by new imaging modalities, magnetic transfer imaging anddiusion tensor imaging, which showed dierences in white-matter integrity and tract coherence inpersons with schizophrenia compared to controls. Oligodendrocytes, in particular, have been the subjectof increased study after gene microarray analyses revealed that six myelin-related genes specic tooligodendrocytes have decreased expression levels in schizophrenia. Oligodendrocytes have also beenshown to be decreased in number in the superior frontal gyrus of subjects with schizophrenia. The MAGknockout mouse, missing a myelin-related gene linked to schizophrenia, may prove to be a useful animalmodel for the dysmyelination observed in the human disease. Studies currently ongoing on this modelhave found changes in dendritic branching patterns of pyramidal cells in layer III of the prefrontal cortex.Further characterization of the pathology in these mice is underway.Received 8 June 2006; Reviewed 5 July 2006; Revised 2 August 2006; Accepted 9 August 2006;First published online 12 February 2007Key words: Myelin, myelin-associated glycoprotein (MAG), oligodendrocytes, schizophrenia.IntroductionA new focus of research has emerged recently in theeld of schizophrenia research. From the dopaminecentred hypotheses that long dominated the eld, anew, more complex view has emerged positing thataltered brain connectivity plays a critical role in thedevelopment of schizophrenia. Several studies haveshown increased neuronal density without increasedabsolute numbers of neurons in a number of brainareas of patients with schizophrenia, implying thatcortical volume is reduced in schizophrenia, possiblybecause of reduced neuropil (Selemon and GoldmanRakic, 1999). In addition, there is a notable absenceof a clear degenerative process in schizophrenia, contrasting sharply with the pathology of neurons seenin other neurological disorders, such as Parkinsonsdisease or Alzheimers disease. It has therefore beenproposed that it is disorganization of specic whitematter tracts that may result in the functional decitsseen in the disease, including impaired workingmemory, cognitive decits, and inappropriate aect.Address for correspondence : Dr P. R. Hof, Department ofNeuroscience, Mount Sinai School of Medicine, Box 1065,One Gustave L. Levy Place, New York, NY 10029, USA.Tel. : 212-659-5904 Fax : 212-849-2510E-mail : Patrick.Hof@mssm.eduIn fact, this hypothesis is supported by several studiesusing new brain-imaging modalities. A major advantage of such approaches is that they can be used tostudy changes in schizophrenia in vivo, allowinginvestigation of dierent stages of the disease andproviding correlates to post-mortem and animalstudies. Magnetic transfer imaging (MTI) measuresprotons bound to macromolecules included in cellmembranes and myelin, and studies using this technique have demonstrated decreased myelin or axonalmembrane integrity in the temporal and frontal lobesof subjects with schizophrenia (Foong et al., 2000,2001; Kubicki et al., 2005). This decrease is particularlycorrelated with severity of negative symptoms (Foonget al., 2001). Diusion tensor imaging (DTI) can beused to measure the vectors of water movement in thebrain. Because water molecules within white mattermove most freely in the direction parallel to the axons,DTI provides a measurement of white-matter tractdirection and, by measuring the strength of the direction vector, tract coherence (Davis et al., 2003). RecentDTI studies have demonstrated decreased anisotropy,implying decreased tract coherence, in several majorwhite-matter tracts in persons with schizophrenia(Buchsbaum et al., 1998; Kubicki et al., 2003, 2005; Limet al., 1999; Sun et al., 2003; Wang et al., 2004). In thethalamus, phosphatidylcholine, the main membrane504D. Segal et al.lipid, and sphingomyelin and galactocerebroside,major myelin membrane components, were also foundto be decreased in schizophrenia (Schmitt et al.,2004), providing additional evidence for a myelindysfunction in the disease. Comparison of schizophrenia with other demyelinating diseases such asmetachromatic leukodystrophy (MLD) and multiplesclerosis (MS) provides further evidence for the existence of dysmyelination in schizophrenia. When MLDis diagnosed in late adolescence and early adulthood,the age when schizophrenia symptoms often appear,this demyelinating disease can present with psychoticsymptoms sometimes indistinguishable from thoseof schizophrenia (Davis et al., 2003). Likewise, patientswith MS who display cognitive and psychiatricsymptoms frequently have white-matter lesions in thefrontal and temporal lobes, which are the brain regionsmost implicated in schizophrenia (Davis et al., 2003).This convergence of symptoms among demyelinatingdiseases aecting the age and brain regions targetedin schizophrenia suggests that a common pathologypossibly exists.The role of oligodendrocytesAs evidence mounted that white-matter tracts arein some way disorganized in schizophrenia, newstudies began to shed light on what that precise defectmight be. A ground-breaking study used gene microarray analysis to examine gene expression levelsin post-mortem dorsolateral prefrontal cortex (PFC)of patients with schizophrenia and matched controls(Hakak et al., 2001). The studys unexpected discoverywas that the expression of six myelin-related genes(MAG, MAL, CNP, HERR3, gelsolin, and transferrin)was signicantly decreased in post-mortem schizophrenia brains. These genes are all predominantlyexpressed in oligodendrocytes. These results, laterconrmed independently (Tkachev et al., 2003; Peirceet al., 2006 in the case of CNP) and extended to otherbrain areas (Dracheva et al., 2006), implied that there isa pathology of oligodendrocytes underlying schizophrenia. This pathology is probably region-specic ;reduced myelin-related gene expression in schizophrenia has been shown in the PFC (Sugai et al., 2004),hippocampus, superior temporal cortex, and cingulategyrus (Katsel et al., 2005), but not in the putamen(Dracheva et al., 2006). Intriguingly, the gene SOX10,an oligodendrocyte-specic transcription factor, tendsto be highly methylated in the brains of personswith schizophrenia, and this correlates with reducedexpression of both SOX10 and other oligodendrocyterelated genes (Iwamoto et al., 2005). These ndingsmay represent an epigenetic indication ofoligodendrocyte dysfunction in schizophrenia, although genetic variations in the SOX10 gene do notappear to aect susceptibility towards the disease(Iwamoto et al., 2006). The myelin oligodendrocyteglycoprotein gene (MOG) is another gene potentiallyinvolved in schizophrenia. One group reported a weakpositive association between MOG gene markers andschizophrenia in the Chinese Han population (Liu etal., 2005), while another group failed to nd any signicant evidence for the MOG gene as a susceptibilityfactor for schizophrenia in the general population(Zai et al., 2005).Still under debate is the issue of whether these geneexpression changes may be due in part to treatmentwith antipsychotic drugs. Drugs that target dopaminereceptors may play a role in altered gene expressionpatterns, because oligodendrocytes express D2 andD3 receptor mRNA and protein at dierent stagesof maturation (Bongarzone et al., 1998; Rosin et al.,2005). Agonists for these receptors provide protectionof oligodendrocytes against glutamate toxicity andinjury after oxygen/glucose deprivation, while antagonists limit this protection (Rosin et al., 2005).Oligodendrocytes also express N-methyl-D-aspartate(NMDA) receptors, which can mediate excitotoxicinjury (Matute, 2006). Indeed, administration to rats ofphencyclidine, an NMDA receptor antagonist that caninduce psychotic symptoms in humans, resulted inaltered expression of many genes, including severalrelated to oligodendrocyte lineage (Kaiser et al., 2004).However, several studies of gene expression in humantissue have not indicated a drug-induced eect ongene expression. Tissue from patients with bipolardisorder showed similar oligodendrocyte-related geneexpression changes to tissue from patients withschizophrenia, even though bipolar disorder is generally not treated with antipsychotic drugs (Tkachevet al., 2003). Additionally, separate analyses of patientswith schizophrenia who were treated and not treatedwith neuroleptic drugs showed no dierences in geneexpression changes (Hakak et al., 2001; Iwamoto et al.,2005; Tkachev et al., 2003). In one study, long-tailedmacaque monkeys treated with haloperidol for 3months did show alterations in glia-related genes, butthe specic genes aected were not all identical tothose altered in humans with schizophrenia (Sugaiet al., 2004).Recent electron microscopy studies have furtherbolstered the hypothesis of oligodendrocyte pathologyin schizophrenia. Studying post-mortem tissue fromthe PFC and caudate nucleus, Uranova and colleagues(2001) have demonstrated apoptotic oligodendrocytesand damaged myelin sheath lamellae formingOligodendrocyte pathophysiologyDensity mapSchizophrenicControlCoefficient of variationFigure 1. Voronoi diagrams of the spatial distribution ofoligodendrocytes in the white matter under area 9 in a controlcase and a schizophrenia case. Each polygon is associatedwith a CNPase-immunoreactive cell. The CV and the localdensities are displayed. The schizophrenia patient displaysless clustering than the control case. Clustering is revealedby more intense red areas and homogeneity by blue areas.The bottom panel shows a dierence in the CV of thespatial distribution of oligodendrocytes in the white matterof area 9 revealing higher homogeneity in schizophrenia.(From Hof et al., 2003.)concentric lamellar bodies in schizophrenia brains,along with irregularities of heterochromatin andmitochondria in oligodendrocytes. With these resultsin mind, our group and others undertook to analyseand quantify the pathology of oligodendrocytes andwhite matter in schizophrenia.Homogeneous cellular distributions are the exception rather than the rule in nervous tissue, an observation not reected in simple counts of specic celltypes in a given brain area. It is specically thecharacteristics of oligodendrocyte spatial distribution,however, that may be relevant to the pathophysiologyof schizophrenia. This is particularly signicant in thecontext of exploring the organizational structure ofwhite matter in order to provide a cellular correlate tothe decreased anisotropy in schizophrenia observedby DTI. To the end of clarifying possible dierencesin oligodendrocyte spatial distribution, we utilized atechnique using Voronoi tessellation maps (Figure 1)to represent oligodendrocyte distribution in postmortem material from the superior frontal gyrus ofpersons with schizophrenia and controls (Hof et al.,2003). Voronoi polygons enclose the region of spacethat is closest to an oligodendrocyte by drawinglines at mid-distance between neighbouring cells andconnecting those lines to form a tessellation of polygons. It is thus the coecient of variation (CV) ofpolygon areas that represents the spatial distribution505of oligodendrocytes. A homogeneous cellular distribution will yield polygons of similar sizes with a smallCV, while a more heterogeneous distribution willresult in very dierently sized polygons and a largerCV of polygon area. The CV thus provides an objectiveestimate of the degree of clustering of oligodendrocytes. When this method was applied to thesuperior frontal gyrus, the CV of polygon area incontrols was 30 % higher than in matched subjectswith schizophrenia. This indicated a more clusteredarrangement of oligodendrocytes in controls, whichmay perhaps contribute to the greater white-mattertract coherence in controls observed using DTI. Inaddition, the density of oligodendrocytes, as calculated from these maps, was 28.3 % lower in subjectswith schizophrenia compared to controls, and therewas a clear correlation between decreased CV ofspatial distribution and decreased local cell density inschizophrenia brains. Absolute numbers of oligodendrocytes were also signicantly decreased in schizophrenia (Figure 2), in both layer III and the whitematter underlying area 9, where the decrease reached27 % (Hof et al., 2003), which is comparable to theresults obtained from the tessellation analyses. In aseparate study of the anterior thalamic nucleus, thenumber of oligodendrocytes was again found to bereduced in schizophrenia, particularly in males (Byneet al., 2006). These results clearly support the notionthat pathology of oligodendrocytes is present inschizophrenia, at least in the frontal gyrus. This regionof the PFC has been shown to undergo changes inschizophrenia (Bouras et al., 2001; Rajkowska et al.,1998; Selemon et al., 1995, 1998). The ndings ofaltered oligodendrocytes in this same region maytherefore indicate that pathology of white matter contributes to the functional and morphometric changesobserved in the disease. We are currently extendingthese studies to other white-matter areas, includingthe anterior cingulate gyrus and temporal areas.Mouse knockout modelsAn acknowledged disadvantage of studying humanpost-mortem material is the generally poor qualityof the tissue, making it on the whole unsuitable forultrastructural studies and ne analyses on the singlecell level, unless materials can be xed within a veryshort post-mortem delay, as was the case in theUranova et al. (2001) study. Animal models of humandiseases provide a way to circumvent the limitationsinherent in studying human tissue. The mouse MAGknockout may serve as a putative animal model forschizophrenia. This particular model was chosen inD. Segal et al.Oligodendrocyte numbers (×106)(a)(b)807060**50403020*100Layer IIIOligodendrocyte densities (×103)5061101009080706050403020100White matter***Layer IIIWhite matterFigure 2. (a) A 28.3 % decrease in oligodendrocyte total numbers was noted in layer III of area 9 in schizophrenics (p


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