Molecular Psychiatry (2008) 13, 245–260 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW The -pathogenesis puzzle in : a literature review G Karoutzou, HM Emrich and DE Dietrich Department of Clinical Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany

Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single or , leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder. Molecular Psychiatry (2008) 13, 245–260; doi:10.1038/sj.mp.4002096; published online 9 October 2007 Keywords: psychosis; ; oligodendrocyte-related genes; susceptibility; epigenetics; white matter

Introduction However, schizophrenia is not solely a genetic disorder. The concordance between monozygotic Schizophrenia is a serious and disabling mental twins, although high, is not 100% and there is disorder that affects approximately 1% of the general consistent evidence across studies of common or population with often devastating effects on the interactive environmental influences on liability to psychological, social and financial resources of the the disorder.4 Hence, an intricate etiology delineated patient, family and larger community. The overt or by several genes each with a small or modest effect positive symptoms of the disorder include auditory and by nongenetic parameters (for example, epige- hallucinations, disordered thinking and delusions, netic processes, environmental factors) seems more while the negative symptoms include avolition, plausible.5 Post-mortem and genetic studies that anhedonia, blunted affect and apathy. Additionally, demonstrate myelin-related abnormalities in schizo- broad areas of functioning are often disturbed includ- phrenia suggest that not only functional, but also ing attention, memory, motivation, thought and anatomical disconnection between brain regions may language processes, social functioning and mood be involved in the disorder.6,7 regulation. In this article, a description of the factors that are Genes undoubtedly play an important role in the associated with schizophrenia is discussed in two etiopathogenesis of schizophrenia. Studies of herit- parts. In the first part we focus on reviewing the ability using twin concordance rates, family and linkage studies and susceptibility genes, so as to have adoption studies, genetic linkage and allelic associa- an account of genetics in schizophrenia. In the second tion analyses have demonstrated a strong genetic part oligodendrocyte-related genes that are involved component underlying the predisposition to develop in the pathophysiology of schizophrenia are dis- the illness.1,2 Genes influence the structure, the cussed. The hypothesis is that oligodendrocytes play preservation and the activity of the neuronal proces- a major role in schizophrenia. sing networks of the brain3 and are partly responsible for the numerous distorted biological and functional processes of the brain that underlie the disorder. Linkage studies and susceptibility genes Due to schizophrenia’s multifactorial-threshold mod- Correspondence: Professor Dr DE Dietrich, Department of Clinical el of genetic liability,8 it is of no surprise that no Psychiatry and Psychotherapy, Hannover Medical School, Carl- single gene or genes have been identified yet as causal Neuberg-Str. 1, Lower Saxony, D-30625, Hannover, Germany. E-mail: [email protected] for schizophrenia. Additionally, several studies have Received 8 December 2006; revised 29 June 2007; accepted 16 failed to replicate previous findings and positional August 2007; published online 9 October 2007 cloning did not achieve a genome-wide level of Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 246 significance, probably as a result of a combination of C-terminal PDZ (PDZ is an acronym combining the first inadequate sample size, a low effective range of genes, letters of three —post synaptic density tissue heterogeneity and methodological differences.9 (PSD95), Drosophila disc large tumor suppressor In spite of these difficulties and problems with (DlgA), and zonula occuldens-1 protein (zo-l), are replicating linkage claims, some consistent patterns protein-interaction domains that are often found in have emerged in recent years. multi-domain scaffolding proteins) ligand of the neu- Several independent linkage studies have sug- ronal nitric oxide synthase gene, failed to replicate an gested a number of loci where positive correlations allelic or association with schizophrenia.22 are found repeatedly. The chromosomes with multi- ple overlapping findings are 1, 2, 4, 5, 6, 7, 8, 9, 10, 13, Chromosome 2 15, 18, 22 and the X.10 In order to identify specific Convergent results from several linkage and associa- disposition genes for the disorder, several researchers tion analyses highlight the significance of chromo- have undertaken detailed mapping studies of linked some 2 for the liability to schizophrenia.10,23 Interest regions and subsequent haplotype (a combination in this chromosome was initiated by the report of a of SNPs; single nucleotide polymorphisms).5 The balanced 2:18 (q21; q23) translocation in affected following enters into this topic more analytically. individuals.24 Moreover, a relatively recent family- based association analysis of affected children and Chromosome 1 adolescents with childhood-onset schizophrenia sup- Regions in both short (p) and long (q) arms have given ports that the glutamate decarboxylase 1 gene, which positive signals in several genome scans.10–12 One lies on 2q31.1 and encodes for a g-aminobutyric acid of the two major chromosomal abnormalities that (GABA)-synthesizing enzyme, may be a candidate have been associated with schizophrenia concerns a risk factor for schizophrenia.25 A neighboring gene, balanced chromosomal translocation t(1; 11) (q42; the distal-less 1 is also an attractive q14.3) which showed strong evidence for linkage to a disposition gene for the disease due to its role in the broad spectrum of phenotypes comprising schizo- differentiation of inhibitory neurons in the forebrain.3 phrenia, and recurrent depres- An intriguing association between locus 2p22.1– sion.1,13,14 A newsworthy finding further supporting p13.2 schizophrenia and type 2 diabetes has been the conditional relation of the translocation with the suggested, indicating a shared biological susceptibil- disorder is the prolonged latency and the reduced ity for these two diseases.26 amplitude of auditory P300 ERP (event-related po- tential) shown in translocation carriers.15,16 Abnormal P300 is an indicator of deficient central information Locations of positive results on chromosome 3 have processing and can be used as a trait marker for the been recorded, although it is not one of the most risk to develop mental disorders rather than reflecting replicated chromosomes.10 Nevertheless it remains an the presence of symptoms.16 The translocation was interesting candidate for the genetic research of found to disrupt two genes on chromosome 1: schizophrenia due to the mapping of the dopamine disrupted-in-schizophrenia 1 and 2 (DISC1 and DISC2), D3 gene (DRD3) on it, a receptor that plays a respectively.13 The DISC2 gene is antisense to DISC1, role in cognitive and emotional functions. This gene and appears not to be translated into a protein.17 has been supported as a contributor to the predis- Subsequent candidate genes from this region are the position to schizophrenia by a meta-analysis of translin-associated factor X (TSNAX) and the DISC1, genetic association studies of variants with a single with the latter showing promising, but not yet compel- associated allele or genotype, in which different ling evidence as a susceptibility gene for the disorder.14 polymorphisms in the same gene were regarded as The TSNAX gene is a third gene in very close separate associations.27 A follow-up linkage study,28 proximity. Another candidate gene less well replicated using a larger number of SNP markers, reported is the regulator of G-protein signaling 4,18 which also replication of the involvement of the 3q29 locus in maps on this chromosome and specifically on 1q23.3, a the liability to schizophrenia. Two linkage analyses region positively associated with schizophrenia.1,3,19 applied on different isolated populations revealed an Recent findings also implicate the 1q32 locus for association between 3q and affected individuals.29,30 susceptibility to schizophrenia, with the presence of a Further evidence implicating chromosome 3 in the candidate gene, the plexin A2 within this region which susceptibility for the disorder comes from a positive seems to be a modulator of axonal migration and association of affected individuals of the Han Chinese neuronal plasticity.20 Finally, a putative gene that lies population with the cell adhesion molecule with on 1q23.3, the nitric oxide synthase 1 (neuronal) homology to L1CAM (close homolog of L1) gene, adaptor protein (also known as CAPON) due to its which maps on 3p26 and seems to be involved in involvement in N-methyl-D-aspartate (NMDA) receptor axonal growth and synaptic plasticity.31 signaling has produced rather conflicting evidence for its association with schizophrenia among studies, with Chromosome 4 a linkage disequilibrium analysis in the Chinese Han Suggestive evidence of a linkage between schizo- population providing positive results for an associa- phrenia susceptibility and the long arms of chromo- tion.21 Another study though, also using markers at the some 4 also exists.10,12 An association study investigated

Molecular Psychiatry Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 247 for linkage disequilibrium between microsatellite which is involved in neuronal migration, axonal markers of a region on 4p close to the locus that branching and in a signaling pathway that underlies harbors the dopamine receptor D5 gene and major memory formation and synaptic connectivity;49,50 psychiatric disorders showed significant evidence of however, the support is not strong.51 Promising data correlation with schizophrenia.32 A current associa- for the gene encoding metabotropic glutamate recep- tion analysis gave positive results for the involvement tor type 3, which is located on 7q21.1–q21.2 and is of the G protein–coupled receptor 78 gene, strength- associated with prefrontal function,52 supports the ening the role of chromosome 4 in the liability to possibility of this gene being etiologically implicated schizophrenia.33 Finally, a single case report of a de in schizophrenia, but the evidence remains weak.1,3 novo balanced translocation between the short arm of chromosome 4 and the long arm of chromosome 13, Chromosome 8 t(4; 13)(p16.1; q21.31) in a late-onset schizophrenic Linked loci with schizophrenia on this chromosome male patient has provided additional interest in this have been reported mainly on the short arm,10,12,36 but region.34 a recent linkage disequilibrium screen in a relatively isolated population found evidence for linkage re- Chromosome 5 gions on both arms, suggesting a wider field of Several lines of evidence point to the significance of research for chromosome 8.53 On 8p21–p12 lies the chromosome 5 in the liability to schizophre- second of the two most strongly implicated suscept- nia.10,12,35,36 A schizophrenia candidate gene, the ibility genes, neuregulin1 (NRG1),45 although other Epsin 4, which encodes for the clathrin-associated reports could not replicate this finding.54 NRG1 is protein enthoprotin maps on the 5q33 region.37 This associated with synaptic remodeling, neuronal migra- protein has a role in the transport and stability of tion and brain development and appears to influence neurotransmitter vesicles at the synapses and is glutamatergic function through regulation of NMDA probably involved in memory processes.38 Another receptors.55,56 Further, NRG1 has been studied to have interesting candidate gene located at 5q21–q22 is the a key role in neurodevelopmental process in central adenomatosis polyposis coli gene, which has been nervous system (CNS) that includes oligodendrocyte reported to confer risk for schizophrenia and may development.57 Therefore, we further discuss this have a role in the reduced vulnerability to cancer in important gene in more details in the second part of schizophrenia.39 One of the most attractive candidate the article. Meanwhile, other genes at or close to this regions for schizophrenia on 5q31–35 that maps locus58 have emerged as possible risk factors for several GABA(A) receptor subunit genes, recently schizophrenia by positional candidate gene analysis gained positive results for an association with the for example, calcineurin A-g subunit gene (PPP3CC), disorder.40 However, further investigations are war- MSTP131.3,56 ranted considering that a concurrent study in a Japanese schizophrenic population failed to confirm Chromosomes 9 and 10 this.41 Further interest in schizophrenia susceptibility These two chromosomes have also gained strong on this chromosome has been stirred by a case report evidence for association with schizophrenia.10 A of a segmental uniparental isodisomy on 5q32-qter locus near the centromere of chromosome 9 might (the offspring receives two chromosomal homologs be of potential interest, due to reports of rather from one parent) in a patient with childhood-onset frequent pericentric inversions of this chromosome schizophrenia.42 in schizophrenic patients.59,60 Furthermore, a ba- lanced reciprocal translocation t(9, 14) (q34.2; q13) Chromosomes 6 and 7 has been implicated as putative genetic contributor to Linkage studies have provided positive results for schizophrenia and psychosis in general.61 The sug- both arms of chromosome 6,10,36,43 with a preliminary gestion of linkage findings on the short arm of study also linking abnormal ocular motor perfor- chromosome 1036,62 is of particular interest, because mance to a locus on 6q.3.44 One of the candidate genes of the close agreement in location shown by different identified so far with the strongest evidence in its samples, using different diagnostic and analytical favor, is the dystrobrevin-binding protein 1 gene approaches.10 Finally, a relatively recent publication which lies on 6p22.45 Dysbindin is a component of of a genome-wide linkage scan in Ashkenazi Jewish the dystrophin protein complex in postsynaptic families reported a positive linkage peak within a densities in the brain and has important roles in region that houses attractive candidate genes, such synaptic transmission and plasticity.46 High-profile as the 5-hydroxytryptamine (serotonin) receptor 7 claims have also been made for the encoding of trace (adenylate cyclase-coupled) gene and NRG3.63 amine-associated receptor 6 gene, which maps on the 6q23.1 linkage region.47 A current comprehensive Chromosome 11 review highlights the positive linkage and association This chromosome has shown some linkage to schizo- findings regarding this chromosome.48 The long arms phrenia,12 but it has not been well replicated.10 of chromosome 7 have also gained strong evidence for However, this chromosome warrants some further association with schizophrenia.10 Genetic evidence mention as it contains the other breakpoint in the for linkage also exists for the gene (RELN), balanced 1:11 translocation and houses the brain-

Molecular Psychiatry Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 248 derived neurotrophic factor (BDNF), a putative con- patients.73 An interesting study suggested an inter- tributory gene for the illness.64 BDNF is an important action between CHRNA7 and the M5 muscarinic neurotrophic factor for cortical glutamatergic pyrami- receptor to confer susceptibility for the illness, even dal neurons.64 Its altered expression in schizophrenia though the authors acknowledged the limitations of seems to influence the age of onset of the disease, their investigation due to the utilization of a single the responsiveness to treatment and the parietal lobe polymorphism for each gene.75 Nevertheless this volume in patients64,65 rather than the risk for suggestion is worthy of further investigation, con- schizophrenia itself.66 The BDNF receptor TrkB has sidering the minor molecular evidence for the also been found to be altered by in situ hybridization dopamine theory of schizophrenia.36 assessment in the prefrontal cortex of affected individuals and has been suggested to contribute to Chromosome 18 the regulation of GABA-related gene expression and Variations in the DNA sequence of this chromosome thus to an alteration in inhibitory prefrontal circui- seem to be associated mostly with bipolar disorder try.67 Moreover, an investigation of linkage disequili- and may manifest the possible overlap between the brium using 444 microsatellite markers in a Japanese two disorders.10,76 Positive linkage has been reported sample identified 11q13 as a potential liability locus for 18p11,77 a region that hosts the guanine nucleo- for schizophrenia, adding further interest in this tide-binding protein (G protein) gene78 and the area.68 nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) flavoprotein 2 (NDUFV2) gene. Varia- Chromosomes 13 and 14 tions of the promoter region of the NDUFV2 gene have Several molecular studies have replicated linkage been implicated in this conferment of risk for locations on the long arm of chromosome 1310,36 and schizophrenia. This gene encodes a subunit of the highlighted putative susceptibility genes in this enzyme complex 1, which catalyzes the transfer of area.69,70 The D-amino acid oxidase activator (DAOA; electrons in the mitochondrial electron transport formerly known as G72) gene is regarded as a very chain, hence suggesting a mitochondrial dysfunction promising candidate to the genetic risk for the in this disorder.79 Convergent results regarding the disorder.14 On 13q14–q21 the 5-hydroxytryptamine mitochondrial hypothesis80 also emerged in a large- (serotonin) receptor 2A (HTR2A) is present, a gene scale DNA microarray analysis of the brain region that may confer risk for schizophrenia.3 A current corresponding to Brodmann’s area (BA) 46.81 However, study however, using systematic meta-analysis of a these results should be interpreted cautiously due to large number of studies applying multiple methods, the possible impact of medication on the expression of failed to replicate the association of the T102C mitochondria-related genes. Nevertheless, the role of polymorphism of the 5-HT2A gene with schizophre- chromosome 18 in the genetic predisposition to nia71 and it seems that the positive association schizophrenia warrants further investigation. markers for this receptor are not consistent.36 Even though it is not a major replicated chromosome, is mentioned since it is the coex- Chromosome 22 is without doubt the most intensively ecutor of the balanced translocation t(9, 14) (q34.2; investigated chromosome in association with schizo- q13). It appears that the brain phrenia. Highly significant evidence of linkage has neuronal PAS domain protein 3 (NPAS3) is affected emerged from many independent molecular stu- by the translocation and thus has a possible role in dies.10,12,30,36 One of the most robust findings is a the manifestation of psychotic symptoms.61,72 For chromosomal aberration concerning the 22q11 dele- other genes on this chromosome, V-AKT murine tion syndrome (also known as Di George syndrome, thymoma viral oncogene homolog 1 (AKT1), an velocardiofacial syndrome, shprintzen syndrome and arbitrator of neuronal survival in the developing conotruncal anomaly face syndrome).14 Affected in- brain, is a promising vulnerability gene.14 dividuals are predisposed to mental disorders, and a large study of adult patients (n = 50) estimated the Chromosome 15 increased risk for schizophrenia to be 24%.82 Candi- In the search for ’ genetic cause, this date genes from this area for which positive data chromosome has obtained several converging positive have been reported, include catechol-O-methyltrans- results.10,36,62 On the long arm lies an attractive ferase (COMT), proline dehydrogenase (oxidase) 1 candidate gene, the a7 nicotinic receptor gene (PRODH) and , DHHC-type containing 8 (CHRNA7).3,64 Functional variants of this gene may (ZDHHC8).3,13,14 COMT is one of the two principal be responsible for the impaired auditory sensory enzymes that degrade catecholamines such as dopa- gating demonstrated in schizophrenic patients and mine, and there is strong evidence that it affects many of their nonschizophrenic relatives.73 The high dopamine-mediated prefrontal information proces- ratio of tobacco smoking among patients may underlie sing.83 In regard to PRODH, a functional candidate the faultiness of the nicotinic-cholinergic system gene that affects glutamatergic synapses,84 a genome which is manifested as decreased auditory sensory screening of schizophrenic individuals, in which gating.74 Moreover, one could speculate that smoking a detailed examination of the complete genomic is an attempt to self-medicate in schizophrenic sequence of PRODH was performed, revealed no

Molecular Psychiatry Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 249 suggestive indication of association.85 Nevertheless The genetic linkage results seem to be replicate in the potential involvement of this gene can not be some cases and in others are not. Clearly, we cannot ruled out. draw a fine map to a single locus or gene. None- theless, these findings give evidence for the genetic Chromosome X basis of schizophrenia. The increased interest in chromosome X arose from the observation that in schizophrenic patients the age Oligodendrocyte-related genes associated with of onset, symptomatology, course of illness and schizophrenia response to treatment are gender related.86 Further- more, according to an interesting theory, schizophre- In recent years, researchers have begun to focus on the nia may be the result of the hominid evolution and potential role of white matter, myelin, and oligoden- the acquisition of language, both of which are related droglia in the pathophysiology of schizophrenia. The to brain lateralization and hemispheric dominance.87 cognitive dysfunctions of schizophrenic patients Anomalous cerebral asymmetry has also been re- may be the result of a functional disconnection in ported in affected individuals at their first episode, both local neural circuitry and that spanning several indicating that a genetic factor is more likely to be brain areas.100 Hence, schizophrenia may be viewed accountable for this characteristic rather than post- as a disconnectivity syndrome100,101 due to distur- natal factors or medication.88 The speciation of bances in myelination, with the aberrant white humans seems to have occurred by an X–Y transloca- fasciculi leading to impairment of electrical insula- tion roughly 3 Myr ago that gave rise to the Homo tion of nerve and consequently, to abnormal sapiens-specific region of Xq21.3 and Yp11.2 homol- transfer of electrical currents along the axons and of ogy.89 Taking into account the above observations and information across the brain regions.102 In order to possibilities, several investigators have tried to find substantiate this theory, DNA microarray analyses possible linkage loci and susceptibility genes for have been performed in post-mortem brain regions schizophrenia within the Xq21.3/Yp11.2 region of of patients and healthy individuals in an attempt homology.10 The results of these studies show a to investigate the differential expression of myelin- somewhat weak association that probably has an related genes. epigenetic background rather than arising from In a microarray analysis7 of post-mortem tissue sequence-based variations.90,9 Information on the from the dorsolateral prefrontal cortex, which has most convincing disposition genes of the aforemen- been implicated in the pathology of schizophrenia,103 tioned is given in Table 1. more than 6500 genes were compared from 12 chronic In order to address the limitations of the studies, schizophrenic and 12 control subjects, and of these, two meta-analyses of schizophrenia linkage have been 89 genes met criteria for altered expression in done,96,97 and obtained to some degree overlapping schizophrenia. Of these 89 genes, only 17 were results. Badner and Gershon96 relied on published decreased in schizophrenia and 6 of these were data that had been analyzed using different methods related to myelin and/or oligodendrocytes. The down- and found support for the existence of susceptibility regulated genes were myelin and lymphocyte protein genes on chromosomes 8p, 13q and 22q for schizo- found in chromosome 2qcen-13, 20,30-cyclic nucleo- phrenia. On the other hand, Lewis et al.97 applied a tide 30 phosphodiesterase (CNP) in chromosome rank-based genome scan meta-analysis, consisting of 17q21, myelin-associated glycoprotein (MAG) in data collected using identical methods across many chromosome 19q13.1, transferring in chromosome studies, both published and unpublished and favored 3q21, gelsolin in chromosome 9q33–34, and the 2q. Several loci emerged: 5q, 3p, 11q, 6p, 1q, 22q, 8p, v-erb-b2 erythroblastic leukemia viral oncogene 20q and 14p (in decreasing order of significance). The homolog 3 (also known as HER3), a neuregulin 8p and 22q regions were supported by both meta- receptor (96). As mentioned before, NRG1 has a key analyses. Besides the well-replicated loci, chromoso- role in neuronal migration and specification,104,105 mal regions that have not achieved extensive con- GABA and glutamate receptor expression106 and in firmation of positive linkage to the disease also synaptogenesis and synaptic plasticity in the CNS.107 emerged, such as 3p, 11q, 14p and 20q. Further, it shows trophic and mitogenic effects in In one of the largest systematic genome-wide oligodendrocyte progenitor cell (OPC) cells in vitro.108 linkage scans of schizophrenia, one region in chromo- NRG1 null mice were found to be deficient some 10 satisfied genome-wide criteria for linkage in development of OPC.109 NRG is important in and two others were highly suggestive: 17p11.2–q25.1 oligodendrocyte development and maintenance in and 22q11.98 Evidence for linkage of 6q15, 12q24 and which it directly/indirectly plays a role in the 20q12, but not for 6q24–22, 1q21–22, 13q32–34 and etiology of schizophrenia. Corfas et al.,110 have 8p12–22 was also reported. It is notable that the proposed a molecular and cellular basis of NRG1- region 12q24 is a novel linkage locus;99 yet the gene erbB: NRG1 regulates radial glia formation, neuronal encoding DAO is located close to this area and migration, neurotransmitter receptor expression, appears to be a contributory factor to the illness oligodendrocyte development and myelination; thus, through its interaction with DAOA.14 Nevertheless, it might be the intermediate molecule to block any of further investigation of this locus is required. these to develop schizophrenia as it is observed in

Molecular Psychiatry Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 250 Table 1 Summary of the most convincing disposition genes in schizophrenia

No. Name Locus General function Divergence in schizophrenia cases

1 DTNBP1 6p22.3 Is expressed by many neuron populations; Decreased gene expression in DPFC3 pyramidal neurons in the hippocampus and Reduced presynaptic dystrobrevin- DPFC, substantia nigra, striatum3 independent fraction of dysbindin, in the Binds to both a- and b-dystrobrevin, which are hippocampal glutamatergic neurons13 components of the DPC13 Susceptibility may depend upon Is involved in PSD functions: trafficking, variation affecting mRNA expression or tethering of NMDA, nicotinic and GABA processing (cis-acting polymorphisms)1 receptors3 Confers risk by presynaptic effects on May play a role in the formation and glutamate trafficking or release1 maintenance of synapses3 May influence the uptake of glutamate into synaptic vesicles13 2 NRG1 8p22–p11 Is detected in neurons in hippocampus, NRG1 defects may alter GABAergic cerebellum, neocortex, some subcortical nuclei3 function (Glutamatergic theory)92 On cellular level, is observed in cell bodies, Abnormal radial glial development may dendrites and axonal projections3 lead to wrong placement and impaired The most predominant NRG1 receptor in the connectivity of neurons brain is ErbB492 (Neurodevelopment theory)92 Influences gliogenesis and neuronal migration (it NRG1 defects may decrease the acts as an inhibitor of myelination92) expression of myelin and In the adult brain it affects the expression and oligodendrocyte-regulated genes92 activation of neurotransmitter receptors: NMDA (via actions on ErbB receptors) and GABA receptors, Ca2 þ -activated K þ channels92 Regulates radial glial cells and modulates their development into astrocytes92 Is involved in regulating synaptic plasticity92 3 RGS4 1q23.3 A GTPase activator that negatively modulates G The reduction in RGS4 mRNA in protein–coupled receptors3 schizophrenia patients may not be Is abundant in the cerebral cortex and in lower evidence for association with the disorder levels in thalamus, basal ganglia3 (decreased RGS4 also in Alzheimer’s Affects signal transduction disease)3 Is involved in neuronal differentiation3 The downregulation of ErbB3 in the Is under dopaminergic regulation3 schizophrenic brain might be an indirect Interacts with ErbB3 (a NRG1 receptor)1 proof of the possible role of RGS4 in the disorder1

4 GRM3 7q21.1–21.2 Is expressed in several neuron populations The SNPrs6465084 monitors a functional (e.g. astrocytes and oligodendrocytes), mainly variation in GRM3 and is associated with presynaptic localization3 decreased expression of presynaptic Is a receptor for N-acetyl-aspartyl-glutamate, and vesicular markers52 N-acetylaspartate is related to mitochondrial The prefrontal N-acetylaspartate activity and to glutamate levels52 reduction may reflect an alteration in Is a heteroceptor modulating serotonin and glutamate neurotransmission or dopamine transmission3 innervation52

5 DAOA 13q34 DAOA is expressed in the caudate and Increase of DAO mRNA in DPFC in (G72) 12q24 amygdala1 and enhances the activity of DAO. schizophrenia3 and DAO DAO is localized in astrocytes (in rat brain)3 DAOA variations are related to prefrontal DAO in the human brain oxidizes D-serine, an and hippocampal dysfunction in activator of NMDA glutamate receptor1 schizophrenia3 Both genes influence risk of schizophrenia through a similar pathway via altered NMDA-receptor function1

6 BDNF 11p13 Is synthesized by pyramidal neurons throughout A polymorphism at nucleotide 196 layers II, III, V and VI in the DLPFC of primates produces an amino-acid substitution and is a neurotrophic factor for cortical (val66met). The met allele may add to the glutamatergic pyramidal neurons64 cognitive impairments seen in Is expressed in fetal cortical subplate that schizophrenia patients66 coordinates cortical neuronal migration, axonal BDNF–TrkB signaling influences the growth and connectivity65 development of cortical GABA neurons BDNF receptors (trkB) are prominent in the and the expression of GABA-related developing fetal brain65 genes67 BDNF facilitates human learning and memory Certain BDNF alleles may relate to age at

Molecular Psychiatry Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 251 Table 1 Continued

No. Name Locus General function Divergence in schizophrenia cases

via its actions in the hippocampus66 disease onset, responsiveness to Mediates neuronal cell survival and apoptosis65 treatment and parietal lobe volume64 Responses to neuronal stressors or insults (e.g. BDNF gene may be an important hypoxia)65 downstream target of one or more Influences the differentiation of serotonergic and schizophrenia susceptibility genes64 dopaminergic neurons65 Is critical for the formation of excitatory synapses64 7 DISC1 1q42.1 Is prominent in limbic structures3 and localized Allelic variations are overtransmitted in in mitochondria, cytoplasm, nuclei, neuritis and schizophrenia93 plasma membranes The Ser allelic is associated with altered Interacts with centrosome and cytoskeletal hippocampal structure and function in proteins, proteins that are involved in membrane healthy subjects93 trafficking of receptors, signal transduction The mutation of DISC1 fails to bind to proteins and possibly proteins with association NUDEL, a protein essential for cortical in mitochondrial function93 development, neuronal migration and The presence of DISC in multiple types of growth1 synapses is suggestive of its involvement in Evidence for enhanced nuclear DISC1 corticocortical and thalamocortical protein expression in schizophrenic connections17 brain13 Affects neuronal migration, neurite architecture and intracellular transport1 8 COMT 22q11.2 Encodes for an enzyme that catalyzes the One of the COMT SNPs, the val158met methylation of dopamine, norepinephrine and allele impacts on the stability of the catecholoestrogens3 enzyme (val-COMT has lower activity Exists in membrane-bound (MB) (in human than met-COMT)3 brain) and soluble (S) (in peripheral tissues and Val158met impacts upon level of COMT in rodents) forms. The MB–COMT has greater mRNA (greater in the deep than affinity for dopamine3 superficial laminae)3 Is more abundant in the prefrontal cortex and Frequent association between the val hippocampus than in the striatum or in allele and illness (it confers higher brainstem dopamine neurons3 activity and thermal stability to COMT)1,3 Is implicated in cortical interneuronal The Val/Met polymorphism is associated monoaminergic signaling and associated with with reduced performance in tests of functions in the PFC3 frontal lobe function1 Prefrontal neurons inhibit striatal DA The Val allele may generate cortical projections, presumably through GABAergic dopamine deficiency and mesolimbic interneurons64 hyperdopaminergia in schizophrenia3 Via the many links between dopamine and A recent meta-analysis reports no amino-acid transmitter systems, it might affect evidence for association with the val other synaptic populations, including allele94 glutamatergic ones5 COMT is more strongly associated with schizophrenic female patients3

9 PRODH 22q11.2 Is a mitochondrial enzyme and is involved in the Evidence of associations of PRODH SNPs energy transfer95 with the disorder5 Influences the regulating of proline levels, which The pseudogene of PRODH2 contains in turn influence glutamate and some of the missense SNPs that are release1,3 associated with the disorder; the PRODH2 variation might be the result of conversion between the real and pseudogene sequences3 The PRODH knockout mouse has abnormalities of sensorimotor gating similar to those in schizophrenia1 Hyperprolinemia, due to PRODH deficiency may be weakly associated with schizophrenia

Abbreviations: BDNF, brain-derived neurotrophic factor; COMT, catechol-O-methyl transferase; DLPFC, dorsolateral prefrontal cortex; DPC, dystrophin-associated protein complex; DTNBP1, dystrobrevin-binding protein 1; GRM3, metabotropic glutamate receptor type 3; Met, methionine amino acid; NRG1, neuregulin 1; PFC, prefrontal cortex; PRODH, proline dehydrogenase; PSD, postsynaptic density; RGS4, regulator of G-protein signaling 4; Ser, serine amino acid; SNP, single nuclei polymorphism; Val, valine amino acid.

Molecular Psychiatry Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 252 schizophrenic patients. Information on these genes screen of the temporal cortex (middle temporal gyrus and their functions is given in Table 2. corresponding to BA21).102 In this interesting study, Other gene families were also found to be altered in the finding of a reduced expression of the period this microarray study,7 including genes involved in homolog 1 gene (known as circadian pacemaker brain development and plasticity, neurotransmission protein gene) introduces the notion of an abnormal and receptors, GABA signaling, the cytoskeleton, in schizophrenia and should in- channels and transporters. MAG has been suggested spire further investigation. as a susceptibility gene for the disorder by other Replicated results also come from Aberg et al.,129 independent studies, in which a positive association who examined tissue samples from the frontal cortex, was found between the gene and schizophrenic BA8 and the left side of the frontal gyrus. In a patients in the Chinese Han population.119,120 microarray analysis conducted by Dracheva et al.,130 Consistent evidence for an oligodendrocyte dys- the mRNAs of MAG, CNP, SOX10 (sex-determining function in the disease also emerged from two other region Y-box containing gene 10), CLDN11 and studies, in which levels of gene expression were peripheral myelin protein 22 were reduced in the assessed in the prefrontal cortices of schizophrenic hippocampus and anterior cingulate cortex, but not in patients.121,118 Tkachev et al.118 further reported the putamen of patients with schizophrenia. These significant downregulation of proteolipid protein1 findings support the notion that the altered expres- (PLP1), which maps at chromosome Xq21.3–q22 and sion of oligodendrocyte and myelin-related genes in mediates axonal–glial interactions, oligodendrocyte schizophrenia is brain region-specific rather than transmembrane protein (CLDN11), which is the third global, which would indicate a cellular functional most abundant myelin protein in the CNS after PLP1 impairment rather than a loss of oligodendro- and myelin basic protein (MBP). MBP was also found cytes.118,129,131 to be downregulated. The reduced levels of MBP (it In a remarkable molecular study by Katsel et al.,132 functions as a microtubule-stabilizing protein in gene expression was analyzed in multiple cortical mature oligodendrocytes122) attain further support regions as well as in the hippocampus, caudate from a study that evaluated its expression in the nucleus and putamen of post-mortem schizophrenic hippocampus and found it to be decreased in female and control brain samples. The most altered tran- subjects with schizophrenia.123 Moreover, an investi- scripts were those encoding for proteins involved in gation of the myelin proteins with nonequilibrium gel determination of glial delineation, myelin structure electrophoresis,124 a technique that reveals myelin and adhesion proteins participating in axoglial con- proteins (MBP, proteolipids and basic Wolfgram pro- tacts. These abnormalities in schizophrenic brains teins) and many other unidentified major basic were most pronounced in the hippocampus, superior proteins, reported equivalent results. Further evidence temporal and cingulate cortices. Confirmation of for the downregulation of PLP1 in schizophrenic these gene expression abnormalities in several in- individuals comes from a family-based association dependent studies102,129,132 with different brain sam- study in 487 Chinese Han family trios.125 Myelin ples and techniques provides very strong evidence for oligodendrocyte glycoprotein (MOG), which is both a oligodendrocyte dysfunction in schizophrenia. target antigen for myelin-destructive antibodies in Another critical gene for the etiopathogenesis of autoimmune CNS demyelization disorders and a cell- schizophrenia is Nogo (also known as , surface marker for oligodendrocyte maturation, was RTN4, NI 250 or RTN-X), a myelin-associated protein also shown to be downregulated in the study by which inhibits the outgrowth of neurites and nerve Tkachev et al.118 and in Han Chinese samples.126 terminals.133 It maps on chromosome 2p13–14, a However, no evidence for association with schizophre- locus strongly associated with schizophrenia97 and nia was reported for MOG in Caucasian samples.127 is expressed by oligodendrocytes in CNS-myelinated In addition, Tkachev studied oligodendrocyte- tissues during neurodevelopment.134 Novac et al. related genes that differentiate between mature and reported that the mRNA of Nogo was overexpressed progenitor cells (that is, platelet-derived growth factor in the frontal cerebral cortex of schizophrenic receptor and NG2 proteoglycan). He reported that patients,135 suggesting a role for Nogo in abnormal neither gene was changed in schizophrenia, suggest- neuronal organization in schizophrenia. Although ing that the downregulation of the myelin-associated subsequent studies136,137 failed to replicate the asso- genes addresses mature oligodendrocyte marker ciation with the polymorphism in Nogo, an investiga- genes. Moreover these genes encode for proteins, tion by Tan et al.138 reported a gender-specific which are located in the major dense line of myelin association of the polymorphism with schizophrenia. and represent transmembrane-spanning proteins. In addition, Covault et al. failed to replicate Novak’s Hence, this downregulation might lead to a defect in results, but showed a racial difference in the myelin compaction.118 Abnormalities in the expres- frequency of the polymorphism.139 Novak reevaluated sion of myelination-related genes in the prefrontal the results of her previous investigation, using a more cortex of affected individuals have also been re- accurate method, a larger set of matched samples, and ported.128 found an upregulation of the isoform Nogo C in Downregulation of several of the oligodendrocyte- schizophrenia.140 Convergent evidence for the role of related genes has also been shown in a genome-wide the Nogo gene in schizophrenia also comes from

Molecular Psychiatry Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 253 Table 2 Summary of the oligodendrocyte-related genes in schizophrenia

No Name Locus General function Divergence from normal function

1 MAG 19q13.1 A member of the immunoglobulin superfamily MAG-deficient mice show delayed and important component of myelin111 myelination and hypomyelination, but Is expressed only by myelin-forming cells, when the latter is not associated with a loss of oligodendrites initiate contact with axons oligodendrites111 (a regulator between myelinating cells MAG-deficient mice demonstrate an and axons)111 age-dependent dysfunction in Mediates oligo–oligodendrite and myelin98,111 oligo–neuron adhesion111 Downregulation of the MAG protein Provides a trophic signal to oligodendrites, has been shown at anterior frontal without which oligodendroglial deterioration cortex113 occurs101 Regulates the properties of sodium channels at the nodes of Ranvier111 MAG protein binds to the Nogo-66 receptor and inhibits axonal growth in vitro112 2 MAL 2qcen-13 Is expressed only when myelin compaction Transgenic mice with increased MAL occurs111 gene dosage revealed alterations of Is localized close to structural proteins (MBP and axon–glia interaction115 PLP1)111 MAL-deficient mice show defects in It may have functional contact with myelin the maintenance of multiple domains glycosphingolipids114 of myelinated CNS axons, indicating Organizes and stabilizes myelin via adhesion114 aberrant protein trafficking115 MAL-deficient mice demonstrate major alterations on the structural level (e.g. aberrant inclusions of cytoplasm within compact CNS myelin).116 3 CNP 17q21 Is a transmembrane protein synthesized by Knocked out mice to CNP gene display oligodendrites very early in myelination central nervous system pathological process98 characteristics reminiscent of some Is not present in compact myelin111 features observed in schizophrenia May play a role in the modulation of cell-surface (reduction in overall brain size, morphology111 enlarged ventricles, and corpus Interacts with mitochondria117 and has a role in callosum atrophy)117 intracellular communication and signal transduction cascade111 Is associated with myelin formation and maintenance111 Is subject to cis-acting influences on gene expression117 4 TF 3q21 An iron-transport protein, not specific Iron deficiency has been shown to to the CNS111 result in immature oligodendrocytes in Is an early marker of oligodendrite rodents and was correlated with differentiation111 downregulation of Tf mRNA118 Has a survival and trophic impact on oligodendrocytes and neurons111 Oligodendroglia contain TF receptors111 5 GSN 9q33–34 Encodes for a cytosolic protein and is expressed The reported downregulation of in developing oligodendrocytes and neurons111 gelsolin in schizophrenia cases might Via regulation of the cytoskeleton: directs and contribute to ongoing glutamate- stabilizes axons and dendrites, cell shape, size induced injury in oligodendroglia and and polarity neurons Is involved in the apoptosis of oligodendrites7 Affects glutamate excitotoxicity111 6 ErbB3 12q13 Is a receptor-protein tyrosine kinase with high Decreased expression of ErbB3 may affinity for neuregulin 1111 limit the function of neregulin 1, and Is involved in cell survival, migration and thus affect oligodendrocytes (neregulin differentiation in both neural and nonneural promotes oligodendrocyte survival and cells111 the proliferation of their precursor cells in culture)

Abbreviations: CNP, 20,30-cyclic nucleotide 3 phosphodiesterase; ErbB3, neuregulin receptor; GSN, gelsolin; MAG, myelin- associated glycoprotein; MAL, myelin and lymphocyte protein; MBP, myelin basic protein; PLP1, proteolipid protein 1; Tf, transferring.

Molecular Psychiatry Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 254 studies which have evaluated the reticulon 4 receptor maturation and normal functioning of the brain and (RTN4R) gene (also known as Nogo-66 receptor).141 the role of dysmyelination for the pathological path- This gene encodes for a functional cell-surface ways of the disorder. receptor, a GPI-linked protein, which is implicated Magnetic resonance imaging (MRI) findings in in axonal growth inhibition.141 It maps on chromo- patients diagnosed with schizophrenia include lateral some 22q11.2, within the velocardiofacial syndrome’s ventricle enlargement, medial temporal lobe volume locus, and mutations of the RTN4R are associated reduction, neocortical superior temporal gyrus vo- with the disorder. Besides Nogo, two other myelin lume reduction, frontal and parietal lobe abnormal- proteins bind to the RTN4R: MAG and MOG, which ities, global and regional reduction in white matter have already been shown to be related to schizo- volume and subcortical abnormalities affecting the phrenia.112 Hence, both Nogo and its receptor may be basal ganglia, corpus callosum, thalamus and cere- relevant to the pathophysiology of the disorder. bellum.150,151 These findings suggest the involvement The human quaking gene, called quaking homolog of a large number of functionally related brain KH domain RNA binding (mouse) (QKI), has also regions. The most frequent positive findings in emerged as a potential susceptibility factor, consider- schizophrenia studies are decreased fractional aniso- ing that it is suspected of regulating the alternative tropy (FA), along with increased diffusivity within splicing of MAG, PLP1 and MBP in mice. The prefrontal and temporal lobes, as well as abnormal- function of QKI has not been studied in humans, ities within the fiber bundles connecting these but the mouse homolog is involved in neural devel- regions (including uncinate fasciculus, cingulum opment and myelination.142 Aberg et al.129 demon- bundle and arcuate fasciculus).152 Altered FA values strated that disturbed expression levels of six in the splenium of the corpus callosum in affected oligodendrocyte-related genes MAG, MBP, PLP1, TF, individuals153,154 and internal capsule diffusion ab- SOX10 and CDKN1B were strongly associated with normalities155 have been detected. Moreover, differ- disrupted relative expression of two splice variants ences in the cerebellar peduncles in schizophrenia QKI-7kb and QKI-7kb B in patients. This suggests that compared to controls have been demonstrated with a alteration of QKI-7kb might be the primary cause of decrease of the FA in schizophrenia subjects.114,156 the down-regulation of myelin-related genes observed Two studies have reported widespread diffusion in schizophrenia. Subsequently, the QKI gene is abnormalities in parietal, temporal, prefrontal and suspected of regulating oligodendrocyte differentia- occipital white matter.116,157 The above findings from tion and maturation, and of influencing the myelin several imaging studies provide evidence that the process in the brain. Mutations within the gene in major cognitive disturbances in schizophrenic pa- its regulatory elements or on other genes regulated tients possibly result from deficits of myelination in by QKI may lead to disease manifestation in hu- relevant neuronal structures (for example, corpus mans.143 The involvement of the functional variants callosum) and the resulting disturbances of signal of the QKI gene in the increase of susceptibility to transduction within these structures. schizophrenia is further corroborated by its locus; it maps on chromosome 6q25–6q27, a region that Epigenetics: the meeting point of genes and is strongly associated with vulnerability to the environment disorder.97,144 The role of these genes in the susceptibility to In the race to uncover the pathology of schizophrenia, schizophrenia derives added weight from a number of gene researchers, taking into consideration that the genetic linkage studies that confirm linkage of the expression of oligodendrocyte genes is regulated by a disease to specific loci for these genes.12,145–148 Still combination of oligodendrocyte-specific transcrip- we need more in-depth studies to completely reveal tion factors,158 have focused on investigating these the molecular biology of schizophrenia. transcription factors. Coordinate synthesis of myelin is transcriptionally mediated, so it is important to examine whether these transcription factors show Further evidence for the role of oligodendrocytes abnormal mRNA imprinting. Downregulated expres- and myelin in schizophrenia sion levels were shown for the transcription factors There is evidence that patients with velocardiofacial oligodendrocyte transcription factor 1 and oligoden- syndrome, a good genetic model for investigations of drocyte lineage transcription factor 2, and the high schizophrenia, demonstrate reduced white matter mobility group protein SOX10, which is crucial for anisotropy in frontal, parietal and temporal regions, the final differentiation of oligodendrocytes.118,159 It is as well as in tracts connecting the frontal and worth mentioning that SOX10 lies within a strong temporal lobes, implicating an influence of 22q11.2 susceptibility locus for schizophrenia on chromo- deletion on white matter circuitry.149 Moreover, some 22q11–13. Expression of several major myelin myelination of the prefrontal cortex has been ob- genes, including PLP1 and MBP, is believed to be served to occur in late adolescence and early adult- under SOX10 transcriptional control.118,159 hood, which is typically the age of onset of In a current study though, it was concluded that the schizophrenia,7,118,123 providing an indication of DNA-sequence variations of the SOX10 gene do not the importance of myelination for the continued contribute to susceptibility to schizophrenia.160 The

Molecular Psychiatry Myelin-pathogenesis puzzle in schizophrenia G Karoutzou et al 255 same group of scientists demonstrated that the DNA Gene expression and drug treatment methylation status of SOX10 accounts for its down- A very interesting and important finding in the regulation and oligodendrocyte dysfunction in investigation of Aberg et al.142 is that the medication schizophrenia.158 The reduced expression of the gene used by patients caused additional modifications in was correlated with an increased percentage of the mRNA levels of QKI: Schizophrenic patients treated methylated allele in brains of patients with schizo- with typical neuroleptics had higher mRNA levels of phrenia. Hypermethylation is known to correlate with the genes’ variants than untreated schizophrenic the silencing of gene expression and transcriptional patients or patients treated with atypical neurolep- inactive chromatin contains-methylated cyto- tics. This result implies an unknown effect of this sines.158,161,162 Aligned to this finding, it has also been class of drugs on the transcription initiation of the suggested that enhanced DNA methylation of the QKI gene, which may have downstream conse- RELN49,50,162 and COMT promoters161 is involved in quences for the myelination pathway.142 Even though their downregulation in schizophrenia. These studies medication is not implicated in the observed altera- indicate that hypermethylation of the promoter of the tions in gene expression in schizophrenia in several genes could provide a molecular basis for the genes’ studies,7,128 the possibility that the expression levels hypoactivity in schizophrenia.49 of some genes may be modulated by medication128,158 DNA methylation status, as well as chromatin cannot be ruled out because of the small sample size remodeling, histone deacetylation and RNA inhibi- of schizophrenic patients off medication that is tion and modification represent epigenetic mechan- used for this kind of analyses. This issue must be isms.163–165 Epigenetics represent a secondary investigated more intensely and with a larger sample inheritance but also a reversible system,95,166 that is of medication-naive patients, in order to obtain suggested as an etiopathogenic factor for complex statistically sound results. mental disorders, such as schizophrenia.167 Altera- tions in DNA methylation might indicate a mechan- ism for DNA flexibility and short-term adjustment Conclusions that enables cells to record the past under various environmental conditions.49 Potential causes of The decipherment of the genetic aspects of schizo- pathological DNA hypermethylation which have been phrenia, one of the most devastating and complex indicated as risk factors for schizophrenia include mental disorders, has reached a turning point. Several some environmental insults, such as ephemeral linkage findings in schizophrenia have been repli- ischemia with a consequent increase of DNA methy- cated and followed by systematic fine-mapping efforts lation, nitric oxide, which has neurodegenerative to identify positional susceptibility genes. These genes effects in focal ischemia, intrauterine environmental are involved in a number of biological processes, conditions and maternal malnutrition, alcohol abuse including synaptic plasticity, neuronal development, during pregnancy, birth and obstetric complications, neurotransmission and signal transduction.7 The vast as well as exposure to drugs and chemicals, hormonal number of reported linkage loci and putative genes status (for example, estradiol, estrogen, steroid hor- mapping on them should not be considered as a failure mones) and viral infections.49,165,168 of genetics to shed more light on the etiopathogenesis of Besides the above data,49,158,161,162 reported down- schizophrenia. On the contrary, they provide evidence regulation of histone deacetylase 3 in the temporal for the genetic background of the disorder and highlight cortex of patients with schizophrenia102 and epige- the necessity of applying more advanced techniques, netic variations in the genes for serotonin 2A utilizing more comprehensive sets of genetic markers, (HTR2A) and the dopamine D3 (DRD3) and D2 more accurate genome sequences, larger samples with (DRD2) receptors163,169 provide further supplementary less broad diagnostic categories, drug-naive patients or evidence for the contribution of epigenetic misregula- patients with matched drug treatment profiles and more tion in schizophrenia. Interestingly, the finding of advanced statistical procedures. different degrees of methylation of the promoter area Implication of oligodendroglia and myelin in of DRD2 between the right and left striatum169 schizophrenia derives from multiple research find- introduces the possibility that the epigenetic mechan- ings. Imaging and neurocytochemical evidence, simi- isms play a role in brain hemisphere laterality165 and larities with demyelization diseases, age-related provides a new interpretation of the reported anom- changes in white matter and myelin-related gene alous cerebral asymmetry in affected individuals. The abnormalities demonstrated in schizophrenic brains epigenetic hypothesis provides a new perspective have been examined in light of the hypothesis that on the etiopathogenesis of schizophrenia and on oligodendroglial dysfunction with subsequent ab- the various non-Mendelian characteristics of the normalities in myelin maintenance and repair con- disease, such as the presence of clinically indistin- tribute to the schizophrenic syndrome.101 guishable sporadic and familial cases, phenotypic Finally, investigations of the epigenetic mechan- variance, discordance of monozygotic twins, coin- isms involved in the regulation of the expression of cidence of peaks of disease onset with major endo- the genes and not only the DNA-sequence variation crine rearrangements and the fluctuating course might help our understanding of the etiopathological of disease severity.167 pathways of schizophrenia.

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