Myelin, myelin-related disorders, and psychosis

SCHRES-06076; No of Pages 9 Schizophrenia Research xxx (2014) xxx–xxx

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Review

Myelin, myelin-related disorders, and psychosis Michelle I. Mighdoll a, Ran Tao a, Joel E. Kleinman a, Thomas M. Hyde a,b,c,⁎ a b c

Lieber Institute for Brain Development, Johns Hopkins Medical Institutions, 855 N. Wolfe Street, Suite 300, Baltimore, MD 21205, USA Department of Psychiatry & Behavioral Sciences, Johns Hopkins Medical School, Baltimore, MD 21205, USA Department of Neurology, Johns Hopkins Medical School, Baltimore, MD 21205, USA

a r t i c l e

i n f o

Article history: Received 28 May 2014 Received in revised form 18 September 2014 Accepted 21 September 2014 Available online xxxx Keywords: Myelin Oligodendrocytes Demyelination Psychosis Schizophrenia White matter

a b s t r a c t The neuropathological basis of schizophrenia and related psychoses remains elusive despite intensive scientific investigation. Symptoms of psychosis have been reported in a number of conditions where normal myelin development is interrupted. The nature, location, and timing of white matter pathology seem to be key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes that could affect neuronal connectivity, which has been implicated as a central abnormality in schizophrenia. Phenocopies of schizophrenia with a known pathological basis involving demyelination or dysmyelination may offer insights into the biology of schizophrenia itself. This article reviews the pathological changes in white matter of patients with schizophrenia, as well as demyelinating diseases associated with psychosis. In an attempt to understand the potential role of dysmyelination in schizophrenia, we outline the evidence from a number of both clinically-based and post-mortem studies that provide evidence that OMR genes are genetically associated with increased risk for schizophrenia. To further understand the implication of white matter dysfunction and dysmyelination in schizophrenia, we examine diffusion tensor imaging (DTI), which has shown volumetric and microstructural white matter differences in patients with schizophrenia. While classical clinical–neuropathological correlations have established that disruption in myelination can produce a high fidelity phenocopy of psychosis similar to schizophrenia, the role of dysmyelination in schizophrenia remains controversial. © 2014 Elsevier B.V. All rights reserved.

1. Introduction The neuropathological basis of schizophrenia and related psychoses remains elusive despite more than a century of scientific investigation. One of the leading hypotheses of schizophrenia posits that early abnormalities in brain development, resulting from the interplay of genetic and environmental risk factors, lead to dysfunction that manifests decades later (Cardno et al., 1999; Singh et al., 2004; Rapoport et al., 2005). Disordered synaptic transmission may be either the cause or result of this abnormal brain development (Stephan et al., 2009). In addition to disordered synapses, symptoms of psychosis also have been reported in a number of conditions where normal myelin development is interrupted (Walterfang et al., 2005). Numerous lines of evidence implicate myelination and factors that affect myelination as critical processes that could affect neuronal connectivity, which has been implicated as a central abnormality in schizophrenia (McClure et al., 1998; Davis et al., 2003; Liddle, 2006; Konrad and Winterer, 2008). Phenocopies of schizophrenia with a known pathological basis involving demyelination ⁎ Corresponding author at: Lieber Institute for Brain Development, 855 N. Wolfe Street, Suite 300, Baltimore, MD 21205, USA. Tel.: +1 410 955 1000; fax: +1 410 955 1044. E-mail addresses: [email protected] (M.I. Mighdoll), [email protected] (R. Tao), [email protected] (J.E. Kleinman), [email protected] (T.M. Hyde).

or dysmyelination may offer insights into the biology of schizophrenia itself. One such factor, abnormal oligodendrocyte function, has been postulated as a primary etiological event in schizophrenia (Hakak et al., 2001; Novak et al., 2002; Davis et al., 2003; Flynn et al., 2003; Tkachev et al., 2003; Aston et al., 2004; Sugai et al., 2004; Iwamoto et al., 2005; Kastel et al., 2005; Dracheva et al., 2006; Georgieva et al., 2006). Disruption of oligodendrocyte integrity in schizophrenia (Davis et al., 2003) has been attributed to decreased total numbers (Vartanian et al., 1999) and a less clustered arrangement of oligodendrocytes in the superior frontal white matter in brains of subjects with schizophrenia (Hof et al., 2003). Abnormal function, structure, or number of oligodendroglia could lead to abnormalities in myelin integrity, including myelin initiation, deposition, compaction, and maintenance, thereby altering the function of myelinated fiber pathways in the brain. Alternatively, the vulnerability of oligodendroglia to the excitotoxic effects of glutamate could have downstream effects on neural transmission due to the role of oligodendroglia in maintaining myelination; by regulating synaptic glutamate concentrations, oligodendroglia can influence the potential excitotoxicity of glutamate on neurons themselves (Davis et al, 2003). Indeed, animal model studies have demonstrated that oligodendroglial-related cell-cycle abnormalities may contribute to pervasive myelin deficits (Kastel et al.,

http://dx.doi.org/10.1016/j.schres.2014.09.040 0920-9964/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Mighdoll, M.I., et al., Myelin, myelin-related disorders, and psychosis, Schizophr. Res. (2014), http://dx.doi.org/10.1016/ j.schres.2014.09.040

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2008). Oligodendroglial and myelin related (OMR) abnormalities in schizophrenia may cause the aforementioned disconnection of neural networks by impairing the saltatory conduction and information conduction from one neuron to others (Roussos and Haroutunian, 2014). This article will review pathological changes in white matter of patients with schizophrenia, as well as demyelinating diseases associated with psychosis. In an attempt to understand the potential role of dysmyelination in schizophrenia, we outline the evidence from a number of clinically-based studies that provide evidence that OMR genes are genetically associated with increased risk for schizophrenia. To further understand the implication of white matter dysfunction and demyelination in schizophrenia, we examine diffusion tensor imaging (DTI), which has shown volumetric and microstructural white matter differences in patients with schizophrenia as compared to controls.

2. Demyelinating diseases and schizophrenia Demyelinating disorders are characterized by the loss of normally formed myelin, and have been associated with psychosis. Symptoms of psychosis have been noted in a number of neurological conditions where normal myelin development and integrity are interrupted, including metachromatic leukodystrophy, adrenoleukodystrophy, cerebrotendinous xanthomatosis, Schilder's disease, Niemann–Pick disease, Pelizaeus–Merzbacher disease, and phenylketonuria (Walterfang et al., 2005). Individuals with these diseases, within a delineated time period in the progression of illness, can manifest psychotic symptoms that are phenocopies of schizophrenia. Metachromatic leukodystrophy (MLD), a rare autosomal recessive disorder of the nervous system with an age of onset related to the degree of arylsulfatase A enzyme deficiency (Polten et al., 1991), begins with pathological lesions in the subfrontal white matter. The progressive demyelination of the periventricular frontal white matter may cause the psychotic symptoms present in MLD (Hyde et al., 1992), as a result of disruption of corticocortical and corticosubcortical connections involving the frontal lobes. The frequency of psychotic symptoms depends on the age at which MLD manifests and on where in the brain the initial disturbance in myelination is most severe (Hyde and Ron, 2011). Psychiatric symptoms are a prominent feature in MLD patients between 12 and 30 years of age (Hyde et al., 1992). The late-onset form (adolescent to young adulthood) of MLD often presents with symptoms consonant with those of acute schizophrenia, including disorganized cognitive processes, delusions, and auditory hallucinations (Finelli, 1985; Alves et al., 1986; Haug, 1987; Terry et al., 1987; Coffey et al., 1992; Hyde et al., 1992; Murphy et al., 1992; Fukutani et al., 1999; Peters et al., 2000); this is followed by progressive mental deterioration with or without focal neurologic symptoms (Davis et al., 2003). As the disease progresses, the appearance of profound neurological deficits helps differentiate clinical MLD from schizophrenia. Hyde et al. (1992) reviewed 129 confirmed MLD cases, of which 53% of cases aged 10–30 years had symptoms of and/or an initial diagnosis of a primary psychotic disorder. As such, MLD with psychosis parallels the age in which schizophrenia appears as a diagnostic entity. Affected MLD patients had similar symptoms to schizophrenia patients: thought fragmentation, catatonic posturing, bizarre gesturing, poor concentration, inappropriate giggling, talking to oneself, and poor insight. Auditory hallucinations were reported in all cases in which hallucinations were mentioned, and auditory hallucinations in MLD were more like those of schizophrenia than auditory hallucinations seen in other neurological disorders. Signs and symptoms indicative of a progressive neurological disorder appeared as demyelination extended to more posterior brain regions (Hyde et al., 1992). These findings suggested that abnormal connectivity and function of the prefrontal regions, at the age when these regions reach full maturation, play a central role in the development of psychosis.

Demyelination in MLD begins with the frontal lobes, often in the periventricular frontal white matter and anterior corpus callosum (Skomer et al., 1983; Schipper and Seidel, 1984; Finelli, 1985; Fisher et al., 1987; Reider-Grosswater and Bornstein, 1987; Waltz et al., 1987). As the illness progresses, psychosis disappears and is replaced by sensorimotor neurologic signs and dementia, as the demyelination spreads throughout the forebrain. From this, Hyde et al. concluded that frontal demyelination is a necessary, but not sufficient, correlate of psychosis in MLD because psychosis is seen only in adolescent/early adult-onset cases even though frontal lesions are characteristic of all MLD cases. Psychosis requires pathological dysfunction of some structures accompanied by intact function of others. In fact, psychosis results from and depends upon dysfunctional connectivity between the frontal lobes and extrafrontal and subcortical structures (Hyde et al., 1992). In MLD, as well as a number of other disorders, adolescence and early adulthood are windows of heightened vulnerability for the development of psychotic behavior, irrespective of the underlying pathological process. Observations concerning the characteristics of psychosis as part of the clinical presentation of MLD offer insight into the mechanisms involved in psychosis associated with primary psychiatric disorders such as schizophrenia. The tendency of MLD to parallel the psychiatric and cognitive presentations of schizophrenia makes it a useful natural model of psychosis, suggesting that psychosis itself may result from dysconnectivity between the frontal lobes and other parts of the nervous system, especially those parts that mature/myelinate earlier in development (Davis et al., 2003). A second demyelinating disease that can present with psychotic features is Niemann–Pick Type C (NPC) disease, an autosomal recessive lipid storage disorder that affects white matter early on but later can extend to gray matter (March et al., 1997; Zervas et al., 2001). In the adultonset form of NPC, cases show white matter disruption in the corpus callosum (German et al., 2002) and periventricular white matter (Josephs et al., 2003). NPC presents initially as psychosis in up to 40% of cases, a rate comparable to MLD (Walterfang et al., 2005). In a study at the Mayo Clinic, Josephs et al. (2003) discovered that of 52 NPC patients, five had an established diagnosis of adult-onset NPC; of these adult-onset patients, two presented with psychoses. In NPC patients, psychotic symptoms include paranoid delusions, auditory hallucinations, visual hallucinations, and disorganization (for review, see Maubert et al., 2013). Hence, adult-onset NPC patients, very much like a subset of MLD cases, may present with schizophrenia-like psychosis depending upon the age of clinical onset. The regional distribution of white matter disruption in both MLD and NPC, strongly associated with psychosis, suggests that interruptions to myelination in frontotemporal, callosal and periventricular fiber tracts are critical to the development of schizophrenia-like psychoses (Walterfang et al., 2005). White matter changes in periventricular and callosal regions have previously been described in schizophrenia (Persaud et al., 1997; Okugawa et al., 2004). Okugawa et al. (2007) showed that compared to healthy subjects, schizophrenic patients had significantly smaller volumes of white matter in the frontal lobe. As disorders with a posterior predominance rarely present with psychosis congruent with the symptoms of schizophrenia, this suggests the importance of connections between, and within anterior regions of, the cerebral hemispheres in the origins of psychosis (Walterfang et al., 2005). In the most classic demyelinating disease, multiple sclerosis (MS), demyelination occurs in unpredictable patches throughout the central nervous system. MS patients have a wide variety of neurologic and psychiatric symptoms; however, they have a very low incidence of psychosis (Beatty, 2002). The low incidence of psychosis in MS may be related to its peak incidence later in life than the typical age of onset for schizophrenia, and due to variability of lesion location. In particular, there is frequent sparing of frontal/temporal regions in MS patients (Davis et al., 2003). When schizophrenia-like psychoses do present in MS patients, frontotemporal disruptions appear “to be the norm” (Walterfang et al.,

Please cite this article as: Mighdoll, M.I., et al., Myelin, myelin-related disorders, and psychosis, Schizophr. Res. (2014), http://dx.doi.org/10.1016/ j.schres.2014.09.040

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2005). These findings support that in neurological myelination disorders, those with a predilection towards frontotemporal white matter tracts, with an age of onset in adolescence or young adulthood, are most likely to be associated with psychotic signs and symptoms. Postmortem samples of the prefrontal cortex (PFC) and caudate nucleus of patients with schizophrenia have also reported myelin abnormalities (Miyakawa et al., 1972; Deicken et al, 1994; Keshavan et al., 1998). Biopsy and autopsy samples have demonstrated ultrastructural alterations of myelin sheath lamellae in the frontal cortex of patients with schizophrenia. Additionally, other identified abnormalities in postmortem samples of patients with schizophrenia include: inclusions between lamellae of myelin sheaths, loss of myelin sheath compactness, and formation of concentric lamellar bodies (for review, see Davis et al., 2003). The temporal onset of psychotic disorders in late adolescence and early adulthood coincides with the concluding myelination of the PFC (Yakovlev, 1948; Lebel et al., 2008; Tamnes et al., 2010). Additionally, patients with schizophrenia have demonstrated visuo-spatial memory and executive functioning deficits (Pantelis et al., 1997), which may be due to conduction defects along frontostriatal circuits and pathways interconnecting brain structures in schizophrenia. Imaging studies also support this notion, and studies have found white matter abnormalities in schizophrenia (Du et al., 2013; Lagopoulos et al., 2013). Such evidence is consistent with the observation that abnormalities in myelin structures may contribute to schizophrenia-like psychoses. 3. Pathological changes of white matter in schizophrenia Both post-mortem and neuroimaging studies have suggested that there are volume reductions and ultrastructural abnormalities in the white matter of the prefrontal cortex in schizophrenia patients (Breier et al., 1992; Buchanan et al., 1998; Sanfilipo et al., 2000; Staal et al., 2000; Sigmundsson et al., 2001; Uranova et al., 2001; Hof et al., 2003; Schmitt et al., 2004; van Haren et al., 2004; Jungerius et al., 2008). Some believe that anatomical white matter changes are intrinsic to the pathological basis of schizophrenia, primarily derived from postmortem and genetic studies of myelin and oligodendrocytes (Highley et al., 1999a, 1999b; Hakak et al., 2001; Uranova et al., 2001, 2004; Hof et al., 2003). In conjunction with neuroimaging findings, post-mortem studies have also found abnormalities in parameters related to white matter in schizophrenia. Absolute numbers of oligodendrocytes were significantly decreased in schizophrenia in cortical areas 9 (Hof et al., 2003) and 24 (Stark et al., 2004), and in the anterior thalamic nucleus (Byne et al., 2008) (for review, see Takahashi et al., 2011). In schizophrenia, the bulk of post-mortem studies suggest that cortical myelin and oligodendrocyte defects are more prominent than subcortical white matter defects (Bartzokis, 2011). A diffusion tensor imaging (DTI) study of the subcortical white matter of younger groups of schizophrenia subjects (mean age: 26 years or younger) showed that abnormalities were not present at the time of onset, but developed as the disorder progressed (Friedman et al., 2008; White et al., 2008; for review, see Bartzokis, 2011). Moreover, white matter defects were associated with longer duration of illness (Bartzokis et al., 2011). Defects in myelination might eventually lead to functional degradation of important neural circuits, and result in cognitive and behavioral inefficiencies and disorganization that are part of the clinical manifestations of schizophrenia (Bartzokis et al., 2011). DTI is an advanced magnetic resonance imaging (MRI) technique used to assess the integrity of white matter tracts in the central nervous system. This technique maps and characterizes the three-dimensional diffusion process of molecules, mainly water, in vivo (Basser et al., 1994). The diffusion of water through tissue is effected by the nature of surrounding tissue. DTI is a noninvasive radiological technique that is particularly useful for imaging white matter tracts in the brain, without affecting the diffusion process itself (Le Bihan et al., 2001). The diffusion of water molecules in the brain ranges from complete freedom in all directions (isotropy) or restricted in particular directions (anisotropy)

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depending on the components of the tissue in a given region. Diffusion anisotropy effects can be fully characterized by DTI to provide the details of tissue microstructure. Anisotropy in white matter reflects better myelinated and organized bundles of axons. Alternatively, significantly reduced anisotropy in the white matter may indicate abnormal white matter integrity, including fiber disorientation, reductions in the number of axons, or disruptions in myelination. DTI has been applied to the study of well-established white matter neurological disorders such as multiple sclerosis (Horsfield et al., 1998; Werring et al., 1999), traumatic brain injury (Sotak, 2002), and the leukodystrophies (Barker and Horská, 2004; Kim et al., 2006). It also has been applied to a variety of neuropsychiatric disorders, including schizophrenia (Kanaan et al., 2005; Kubicki et al., 2007) and autism (Ulay and Ertuğrul, 2009; Travers et al., 2012; Baribeau and Anagnostou, 2013). Studies of white matter pathology in schizophrenia, whether through in vivo neuroimaging or in vitro examination of postmortem brains, are difficult to interpret. Many patients with schizophrenia smoke heavily (Kelly and McCreadie, 2000) and suffer from medication-induced metabolic syndromes (van Winkel et al., 2008). Both cigarette smoking and the metabolic syndrome are risk factors for cerebrovascular disease and stroke (Wolf et al., 1991; Manolio et al., 1996; Isomaa et al., 2001; Rodriguez et al., 2002; Koren-Morag et al., 2005; for review, see Goldstein et al., 2006), which in turn can lead to microinfarctions and disordered perfusion in the subcortical white matter. There are abundant confounding factors that may cause white matter abnormalities that are not intrinsic to the pathobiology of schizophrenia. In both neuropathology and neuroimaging, it is uncertain whether white matter changes are an intrinsic component of schizophrenia or are the consequence of neuroleptic treatment, social deprivation, or other epiphenomena related to suffering from a chronic psychiatric disorder. A number of studies have suggested that the DTI abnormalities in schizophrenia are confounded by multiple factors, including the duration of illness and treatment with antipsychotic medications (Konopaske et al., 2006, 2008), age (Kochunov et al., 2013a, 2013b; Giezendanner et al., 2013; Mandl et al., 2013), sex of the subjects (Savadjiev et al., 2014), and even heavy cigarette smoking (Cullen et al., 2012; Kochunov et al., 2013a, 2013b). A number of studies have concluded that anatomical white matter changes are intrinsic to the pathological basis of schizophrenia, primarily derived from postmortem and genetic studies of myelin and oligodendrocytes (Highley et al., 1999a, 1999b; Hakak et al., 2001; Uranova et al., 2001, 2004; Hof et al., 2003). In support of these neuropathological findings, numerous imaging studies have purported that there are significant abnormalities in the structure and integrity of white matter tracts in multiple brain regions in patients with schizophrenia (Kanaan et al., 2005; Kubicki et al., 2007). However, despite intensive investigation, there has been no emerging consensus upon the exact nature of the white matter dysfunction in these patients (Melonakos et al., 2011; Fitzsimmons et al., 2013). At a neuropathological level, it has been difficult to correlate neuropathological findings with abnormalities on DTI. Studies of schizophrenia patients prior to the institution of neuroleptics may yield a better understanding of pre-morbid white matter changes related to schizophrenia. DTI studies on first episode schizophrenia (FES) patients have shown compromised white matter integrity in cortical and subcortical brain regions, and white matter association and commissural tracts. These investigations support the notion that white matter pathology is present from the earliest stages of illness (Kuswanto et al., 2012). However, DTI abnormalities in first episode patients are less robust than in chronic patients, indicating that other factors may contribute to a progressive loss of white matter following the onset of illness (Peters et al., 2010). DTI studies are extremely valuable, as they offer lines of investigations that are not possible with post-mortem brain studies. DTI investigations can be conducted longitudinally. Moreover, they can be conducted in neuroleptic-naive first episode patients where the diagnosis only becomes clear after a time interval.

Please cite this article as: Mighdoll, M.I., et al., Myelin, myelin-related disorders, and psychosis, Schizophr. Res. (2014), http://dx.doi.org/10.1016/ j.schres.2014.09.040

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Findings from DTI have ratified the focus of postmortem brain studies on fronto-temporal structures. A recent meta-analysis summarized 8 DTI studies with voxel-wised analysis of the FA in FES. This metaanalysis reported consistent FA reductions in the white matter of the right deep frontal and left deep temporal lobes, implicating four white matter tracts (the inter-hemispheric fibers through the anterior corpus callosum, the cingulum bundle, the left inferior longitudinal fasciculus, and the left inferior fronto-occipital fasciculus). The authors concluded that there were abnormalities in the fronto-limbic circuitry at the earliest clinical stages of schizophrenia (Yao et al., 2013). Wang et al. (2011) also reported FA deficits in the right corpus callosum as well as the left temporal lobe of schizophrenia patients. Thirty of the 68 patients in this study were neuroleptic-naïve at the time of DTI, and the remaining 38 patients were on low dose antipsychotics at least 3 days prior to MRI scanning. There are no significant differences in FA values between the neuroleptic-naïve patients and patients on medication (Wang et al., 2011). DTI reports offer additional support to neuropsychology, and volumetric and functional neuroimaging studies that have implicated frontal and temporal lobe abnormalities in schizophrenia. Longitudinal studies on subjects at clinical high risk (CHR) for psychosis provide another opportunity to understand the development of the illness before onset, without the interference from confounds, such as neuroleptic modification. Once again, by following these patients over time, these cohorts can be studied by comparing those that develop schizophrenia with those who do not. This type of retrospective analysis of DTI findings is not possible with conventional neuropathology. Carletti et al. (2012) studied subjects at CHR of psychosis longitudinally, FES patients, and controls using DTI. FES patients showed widespread FA reduction, and white DTI measurements in the CHR group were intermediate relative to FES and controls. A longitudinal analysis revealed a progressive FA reduction in the left frontal white matter in CHR subjects (Carletti et al., 2012). This study provides evidence that a progressive reduction of integrity of white matter may be related to the onset of schizophrenia. The normal changes in white matter tracts during adolescence and early adulthood, which is also a period of high vulnerability for development of psychotic illness, may be a key target in the pathogenesis of schizophrenia (Peters et al., 2012). With conflicting reports in the literature, it may be too early to reach a definitive conclusion regarding the biological processes corresponding to the aforementioned DTI findings in schizophrenia. However, there is an emerging consensus from current DTI findings in patients with schizophrenia suggesting widespread compromise of white matter integrity immediately before or at the earliest stages of illness. There is some evidence of a progressive disruption during the development of the schizophrenia, but it is difficult to separate abnormalities intrinsic to the illness from those imposed by other factors. 4. Genetic association of OMR genes in schizophrenia Meta-analyses have revealed more than a hundred genes or genetic loci associated with an increased risk of schizophrenia (Harrison and Weinberger, 2005; PGC-SWE; Ripke et al., 2013). Many of these genes play an important role in brain development (Weinberger, 1986; Walsh et al., 2008). A number of smaller clinical studies have identified several OMR genes (Jungerius et al., 2008; Jitoku et al., 2011; Ayalew et al., 2012) and myelin-related pathways (Yu et al., 2014) that are associated with increased risk for schizophrenia. However, these latter findings should be looked upon with some skepticism, as the largest and most carefully curated meta-analysis of genetic risk for schizophrenia, the PGC study, did not find any statistical association with any of these loci (PGC-SWE; Ripke et al., 2013). Roussos and Haroutunian (2014) recently published the results for the association of each OMR gene with schizophrenia according to the largest published schizophrenia GWAS dataset (PGC-SWE; Ripke et al., 2013). They reported that no OMR genetic association reached genome-wide significance; however ANK3, ErbB4, and NRG1 all showed a trend towards association (p b 5 × 10−5). From their

perspective, they concluded that the strongest support for OMR genes with genetic association with schizophrenia are neuregulin 1 (NRG1), ErbB4, disrupted-in-schizophrenia 1 (DISC1), reticulon 4 receptor (RTN4R), oligodendrocyte lineage transcription factor 2 (OLIG2), and CNP. As the PGC cohorts expand, it is possible that some of these loci might reach genome-wide significance, but at a current significance level of p b 5 × 10−5, this is rather unlikely. The PGC results to the contrary, some postmortem brain RNA studies have demonstrated that specific myelin-related genes are differentially expressed in patients with schizophrenia (Hakak et al., 2001; Tkachev et al., 2003; Prabakaran et al., 2004; Kastel et al., 2005; Dracheva et al., 2006; McCullumsmith et al., 2007; Barley et al, 2009). However, there are no widely replicated brain RNA findings for white matter associated genes. There may be some degree of genetic heterogeneity, leading to common abnormalities in white matter structure and function. These genetic abnormalities converge upon a similar clinical phenotype, as evidenced by imaging and neuropsychological testing assays. For example, a number of postmortem studies have failed to precisely replicate individual findings, with evidence that expression of some or all of the OMR genes does not differ between patients with schizophrenia and controls (Flynn et al., 2003; Tkachev et al., 2003; Dracheva et al., 2006; McCullumsmith et al., 2007; Mitkus et al., 2008). In contrast, Hakak et al. (2001) found that multiple myelin-related genes were significantly down-regulated in the postmortem PFC of schizophrenic brains compared to controls: myelin-associated glycoprotein (MAG), 2′,3′-cyclic nucleotide 3′-phosphodiesterase(CNP), myelin/lymphocyte protein (MAL), gelsolin (GSN), ErbB3 (aka, HER3), and transferrin (TF). In a microarray survey of published genetic studies of schizophrenia, Davis et al., 2003 indicated that expression levels of these six OMR genes were diminished by up to 50%. The finding that so many biologically related genes were down-regulated suggests the possibility that oligodendroglia, the cell type expressing these genes derive in the brain, are dysfunctional or even undergoing apoptosis (Davis et al., 2003). Furthermore, there are additional post-mortem studies providing support for OMR abnormalities in schizophrenia (Sequeira et al., 2012; Roussos and Haroutunian, 2014; for review, see Fitzsimmons et al., 2013). MAG, a gene expressed only by myelin-forming cells, is involved in the initiation of myelination when oligodendrocytes begin to contact neighboring axons (Davis et al., 2003). Decreased MAG expression in schizophrenia has been confirmed via qRT-PCR (Bahn, 2002; Copland et al., 2002)and cDNA microarray study (Aston et al., 2004). In contrast two post-mortem studies did not find any differences in MAG expression (Flynn et al., 2003; Mitkus et al., 2008). Normally, MAG is found in the periaxonal regions of myelinated axons and in the paranodal region of myelin sheaths. MAG enhances the survival of oligodendrocytes and provides trophic signals to oligodendrocytes helping to prevent their deterioration. MAG-deficient mice have morphologically abnormal myelin sheaths, lack well-developed cytoplasmic collars, contain redundant myelin and non-compact areas of myelin, and have periaxonal areas of degeneration and dystrophy of distal oligodendrocyte processes. At least in part, some of these changes are similar to ultrastructural abnormalities observed in schizophrenia brains (Davis et al., 2003). MAG-null mice also demonstrate age-dependent dysfunction in myelin (Harvey et al., 1999). In a clinical study, Voineskos et al. (2013) recently demonstrated that two MAG SNPs (rs2301600 and rs720309) significantly influence processing speed, visuomotor speed and attention in schizophrenia patients, and visuomotor speed and verbal memory in controls, suggesting the significance of MAG in influencing cognitive performance. In another clinical study, Wan et al. (2005) found that the MAG risk SNP rs720309 was associated with schizophrenia. Specifically, the T/A genotype at rs720309, and the haplotypes rs720309–rs720308, both showed strong association with schizophrenia (Wan et al., 2005; Yang et al., 2005). The authors then suggested that MAG may play a role in genetic susceptibility to schizophrenia, consistent with the hypothesis of oligodendritic and myelination dysfunction in schizophrenia. However, the absence of

Please cite this article as: Mighdoll, M.I., et al., Myelin, myelin-related disorders, and psychosis, Schizophr. Res. (2014), http://dx.doi.org/10.1016/ j.schres.2014.09.040

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this genetic locus associated with a heightened risk of schizophrenia in the PGC study makes these findings less tractable. OLIG2, which encodes the transcription factor central to oligodendrocyte development (Ross et al., 2006), is yet another prime candidate for susceptibility variants with wide-ranging secondary effects on OMR gene expression (Lyudmila et al., 2006). Several studies have reported reduced OLIG2 mRNA in postmortem schizophrenia brains (Tkachev et al., 2003; Iwamoto et al., 2005; Kastel et al., 2005). Postmortem studies performed by Mitkus et al. (2008) revealed that two OLIG2 SNPS, rs1059004 and rs9653711, both previously associated with schizophrenia (Georgieva et al., 2006), predicted lower OLIG2 mRNA expression levels in the DLPFC white matter of patients with schizophrenia. OLIG2 also might affect the expression of many other OMR genes because it influences both precursors of (Lu et al., 2000, 2002; Zhou et al., 2000; Takebayashi et al., 2002) and mature (Gokhan et al., 2005) oligodendrocytes and is both necessary and sufficient for the genesis of oligodendrocytes and myelination (Rowitch et al., 2002; Jakovcesvski and Zecevic, 2005; Copray et al., 2006). Additionally, an interactive effect on schizophrenia risk has been reported for OLIG2 and CNP (p = 0.008) and OLIG2 and ERBB4 (p = 0.4) (Georgieva et al., 2006). OLIG2 expression is also significantly correlated in the cerebral cortex with the expression of CNP and ErbB4, suggesting that variation in OLIG2 might confer susceptibility to schizophrenia as part of a network of genes implicated in oligodendrocyte function (Roussos and Haroutunian, 2014). Although the absence of a signal in OLIG2 in the PGC dataset diminishes the impact of these findings (PGC-SWE; Roussos and Haroutunian, 2014), the findings from other studies cannot be casually dismissed given the volume of data supporting their role in the pathogenesis of genetic risk in schizophrenia. OLIG2-related OMR changes linked to pathophysiological changes in schizophrenia may include alterations in the expression of CNP, an OMR gene critical for oligodendrocyte function. There has been at least one report of a genetic association of allelic variation in CNP with risk for schizophrenia (Peirce et al., 2006). In a Family Based Association Test (FBAT) study of 246 families of primarily European-Caucasian origin, SNP rs2070106 associated with schizophrenia (p = 0.027), and there was a significant maternal parent-of-origin effect for this CNP SNP risk allele for schizophrenia (p = 0.003) (Voineskos et al., 2008). Interestingly, the CNP risk polymorphism has been associated with lower gene expression, which is consistent with CNP dysfunction in schizophrenia (Roussos and Haroutunian, 2014).Several genes associated with heightened risk for schizophrenia, not traditionally associated with myelination or oligodendrocytes, play a role in the maintenance of myelin and myelination. Genetic variation in NRG1 (Stefansson et al., 2002) and ErbB4 – the NRG1 receptor (Norton et al., 2006) – has been linked to increased risk for illness in schizophrenia. The potential pathophysiological role of NRG1 may include its neuro-glial trophic effects and role in myelination (Harrison and Law, 2006). Specifically, NRG1 type III is required for Schwann cell generation (Taveggia et al., 2005), and NRG1– ErbB signaling is essential for the onset of myelination in post-migratory Schwann cells (Lyons et al., 2005). Many groups have reported the association of the NRG1–ErbB4 risk variants with cognitive (Stefanis et al., 2007), electrophysiological (Roussos et al., 2011) and neuroimaging schizophrenia-related outcome variables, including altered frontotemporal brain function (Hall et al., 2006) and white matter density and integrity (McIntosh et al., 2008; Konrad et al., 2009). In post-mortem brains, there is altered gene and protein expression of NRG1 and ErbB4 contrasting patients with schizophrenia and normal controls (Hashimoto et al., 2004; Law et al., 2006; for review, see Corfas et al., 2004, and Roussos and Haroutunian, 2014). While the absence of a signal in NRG1 and/or ErbB4 in the PGC dataset (PGC-SWE; Roussos and Haroutunian, 2014) diminishes the impact of these findings, they cannot be easily dismissed given the volume of data supporting the role of NRG1 and ErbB4 in the pathogenesis of genetic risk in schizophrenia. DISC1 is another gene that has been strongly implicated in clinical risk for schizophrenia and related major psychiatric illnesses (Millar

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et al., 2000, 2001). Dysfunctional expression of this gene may contribute to the OMR-associated abnormalities in schizophrenia. The protein derived from DISC1 acts as a cytosolic scaffold protein for processes such as neurogenesis, neuronal migration, dendritic growth, and synaptic maintenance (Porteous et al., 2006; Brandon et al., 2009; Jaaro-Peled et al., 2009; Hayashi-Takagi et al., 2010; Brandon and Sawa, 2011). Two recent studies in zebrafish have suggested that DISC1 plays a critical role in oligodendroglial differentiation during neurodevelopment (Drerup et al., 2009; Wood et al., 2009). Kastel et al. (2011) found that DISC1 transgenic mice demonstrated premature oligodendrocyte differentiation and increased proliferation of their progenitors. Furthermore, alterations of NRG1, ErbB3 and ErbB4 have been associated with the expression of mutant DISC1 during neurodevelopment, suggesting that abnormal signaling may contribute to the increased expression of oligodendrocytic markers in the forebrain (Kastel et al., 2011). Thus, DISC1 and NRG1 appear to function in common or related pathways to control the development of oligodendrocytes (Herring and Christine, 2011). In the human post-mortem brain, fetal-dominant DISC1 transcripts are up-regulated in the hippocampus of patients with schizophrenia and their expression levels are associated with schizophrenia clinical risk polymorphisms (Nakata et al., 2009; for review, see Roussos and Haroutunian, 2014). Additionally, recent immunocytochemical analyses by Hattori et al. (2014) showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. The expression of myelin related markers (CNPase and MBP) as well as the number of cells with a mature oligodendrocyte morphology were decreased following full length DISC1 overexpression. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin-related proteins and the number of mature oligodendrocytes (Hattori et al., 2014). These findings suggest that DISC1 mutations associated with schizophrenia may exert some of their deleterious effects through dysmyelination. More work needs to be done to clarify the role of full-length and truncated DISC1 isoforms in oligodendroglial proliferation, differentiation, and function. In addition to these clustered positive findings, other genes in the pathway of OMR genes may play a role in schizophrenia pathology. For example, PIK4CA, which maps to 22q11, a chromosomal region consistently linked to schizophrenia through copy number variant studies (Blouin et al., 1998; DeLisi et al., 2002; Sullivan, 2005), and three PIK4CA SNPs have been significantly associated with the risk of schizophrenia in a Dutch cohort in a clinical case–control study (Jungerius et al., 2008). It is possible that aberrant phosphatidylinositol (PI) levels, in part regulated by PIK4CA, may influence the shape of neurons or oligodendrocytes through cytoskeletal regulation (Jungerius et al., 2008), thereby contributing to oligodendroglial dysfunction-induced myelin abnormalities, which contribute to the pathogenesis of schizophrenia (Davis et al., 2003; Uranova et al., 2004, 2007). As mentioned repeatedly throughout this section, many of the genes identified in small clinical cohorts or post-mortem studies have not been associated with increased risk for schizophrenia in the largest study of genetic risk of schizophrenia, the PGC dataset (Ripke et al., 2013). While outright dismissal of the findings from selected clinical studies and/or post-mortem brain analyses may be premature, the findings from such studies should be viewed with caution. Moreover, the findings of classical neuropathological changes such as ultrastructural abnormalities in the myelin sheath on electron microscopy (Uranova et al., 2001, 2004) reinforce the perspective that changes in myelin and oligodendrocyte function may be a primary part of the pathophysiology in schizophrenia. 5. Discussion The functional and structural similarities in psychiatric symptoms and cognitive deficits between adolescent-young adult onset MLD and NPC, and schizophrenia are compelling, especially when considered

Please cite this article as: Mighdoll, M.I., et al., Myelin, myelin-related disorders, and psychosis, Schizophr. Res. (2014), http://dx.doi.org/10.1016/ j.schres.2014.09.040

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M.I. Mighdoll et al. / Schizophrenia Research xxx (2014) xxx–xxx

alongside the increasing imaging evidence for white matter involvement in schizophrenia. The nature, location, and timing of white matter pathology seem to be key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Myelination and factors that affect myelination, such as the function of oligodendroglia, are critical processes that can profoundly affect neuronal networks and connectivity, which have been implicated as abnormalities in schizophrenia (Davis et al., 2003). An important consideration is whether these changes in myelin gene expression or white matter structure are a direct cause of schizophrenia or alternatively, a secondary consequence of abnormal brain function on white matter. Medications or drug abuse can also affect white matter genes and/or white matter structure in some psychiatric patients (Fields, 2008). However, the genetic risk factors involving myelin genes and changes in levels of mRNA transcripts of OMR genes suggest that white matter pathology and OMR changes are primary contributors to disease-specific pathophysiology in schizophrenia. Multiple candidate studies have provided evidence that OMR genes are genetically associated with schizophrenia. Although previously reported reductions in the expression of several myelin-related genes in the DLPFC have not been detected in all studies of post-mortem samples, there is an emerging consensus that individuals carrying risk-associated alleles in some oligodendrocyte-related genes did demonstrate relatively lower transcript levels (Mitkus et al., 2008). Additionally, the products of these same genes have been implicated in numerous direct studies of OMR gene and protein expression in the brains of persons with schizophrenia, as well as, neuroimaging studies, providing a stronger support for causality with the disease. Taken together, the data support the importance of the OMR/white matter pathway of disease in schizophrenia by identifying the key relationships among OMR risk genes, white matter tract integrity, and cognitive performance in this disorder. Role of funding source The authors' research is internally funded by the Lieber Institute for Brain Development (LIBD). There are no manuscript archiving requirements. LIBD will fund open access publishing of this article. Contributors Michelle I. Mighdoll managed the literature searches and analyses. Michelle I. Mighdoll and Dr. Ran Tao wrote the first draft of the manuscript. Drs. Thomas M. Hyde and Joel E. Kleinman assisted in the literature analyses. All authors contributed to and have approved the final manuscript. Conflict of interest The authors declare that there are no conflicts of interest. Acknowledgments We thank Ms. Anna Brandtjen, who kindly helped format the references for our paper.

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