Search tips
Search criteria 


Logo of schbulschizophrenia bulletinsubscriptionscontact uscurrent issuemy basketarchivemy accountsearchcontact this journaloxford journalsabout this journal
Schizophr Bull. 2007 November; 33(6): 1343–1353.
Published online 2007 February 27. doi:  10.1093/schbul/sbm007
PMCID: PMC2779884

EIF2B and Oligodendrocyte Survival: Where Nature and Nurture Meet in Bipolar Disorder and Schizophrenia?


Bipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity.

Keywords: famine, virus, oxidative stress, endoplasmic reticulum stress, schizophrenia, bipolar disorder, oligodendrocyte, eIF2-alpha, eIF2B, translation initiation, protein synthesis, polygenic


Famine, viral infection, heavy metals, and maternal stress during pregnancy or early development have all been suggested as risk factors in schizophrenia, as well as in bipolar disorder.13 Both conditions are characterized by oligodendrocyte cell loss and hypomyelination.46 It has been suggested, in the case of famine, that such stress may result in genotoxic effects, related to folate deficiency, resulting in germ line mutations in important developmental and other genes that might predispose to psychiatric disorders.7 However, the link between such types of stress and schizophrenia/bipolar disorder might also be related to the effects of such stressors on any, or several, of a series of extant polymorphic genes already known to be associated with these diseases (table 1) and to the signaling networks that they control. Certain genes associated with schizophrenia can be grouped into families related to pathology and form a clearly defined signaling cascade related to N-methyl-D-aspartate (NMDA) receptor–dependent long-term potentiation (LTP) and plasticity. Defects in this pathway may underpin a particular endophenotype in schizophrenia, related to impaired glutamatergic function, memory disturbances, and synaptic dendritic poverty.8

Table 1.
A Selection of Genes Reported to be Associated with Schizophrenia and/or Bipolar Disorder

As suggested below, a further set of genes, implicated either in bipolar disorder of schizophrenia, or both, are implicated in a well-characterized pathway that controls protein translation and synthesis. This pathway is activated by growth factors and NMDA receptors and inhibited by the environmental stress factors associated with bipolar disorder or schizophrenia. Genes associated with bipolar disorder and/or schizophrenia encode for many of its component proteins. This network converges on the eukaryotic translation initiation factor eIF2B. While one would not expect a process as universal as translation initiation to affect any particular cell type, mutations in any of 5 eIF2B subunit genes are responsible for vanishing white matter disease which provokes severe loss of oligodendrocytes and astrocytes in early life.9 Thus, the activation of this stress kinase pathway by diverse stressors implicated in the subsequent development of schizophrenia or bipolar disorder converges onto a system, laced with risk-promoting genes, that somehow dictates the fate of cells that die in these diseases.

As a working hypothesis, one might imagine that polymorphic susceptibility genes create a suboptimal functioning of a pathway designed to cope with stress. This pathway influences oligodendrocyte function and the diverse genetic variants render these cells more vulnerable to the effects of the predisposing stressful influences in these psychiatric disorders.


Genes associated with schizophrenia or bipolar disorder were collected by literature survey (table 1). The survey aimed to include all genes for which positive association has been reported and is based on the conclusion of the original authors. It should be appreciated that conflicting association data exist for most of these individual genes. The reasons for this include-all policy relate to an assumption of genetic heterogeneity across populations and within the disease and are discussed in greater detail in a previous review.8 Because of the large number of genes and effects summarized in this review, their individual association, roles, and interactions are summarized on Web site tables harbored at Environmental risk factors as well as a brief summary of the roles of the eIF2-alpha kinase-signaling components are also posted on this site. Genes associated with schizophrenia or bipolar disorder are in bold italics and superscripted (B or S for association with bipolar disorder and schizophrenia, respectively).

Stress-Activated Pathways Inhibit Protein Synthesis and Activate ATF4

Viral infection, glucose or amino acid deprivation, heat shock, heavy metals, as well as oxidative and endoplasmic reticulum stress, activate a common signaling network, whose principal goals are to shut down protein synthesis and to activate defense mechanisms in an attempt to combat these stresses or, if unsuccessful, to activate apoptotic cascades (figure 1). Different types of stress activate specific eIF2-alpha kinases (commonly known as HRI [activated by heme deficiency, nitric oxide {NOS1BS, NOS3B} and oxidative stress], GCN2 (activated by amino acid starvation), PKR (activated by growth factor deprivation, inflammatory cytokines [TNFBS, IL1BBS], bacterial toxins, or viral DNA stress), and PERK (activated by endoplasmic reticulum stress). Each phosphorylates the eukaryotic translation initiation factor eIF2-alpha. Phosphorylated eIF2-alpha inhibits the activity of eukaryotic translation factor eIF2-beta (EIF2B1–EIF2B5), resulting in the arrest of the translation of RNA to protein and a subsequent decline in protein synthesis.8,1013

Fig. 1.
A schematic representation of the main elements of the growth factor and NMDA receptor–activated AKT survival pathway and the stress-activated eIF2-alpha kinase cascade. Factors, or genes (boxes), are color coded according to their reported association ...

This stress-activated pathway also influences the transcription factor, ATF4, which is activated by phosphorylated eIF2-alpha.14 ATF4 controls the transcription of PTGS2S and GCH1B as well as a series of stress-related defense or apoptosis-related pathways via its interactions with transcription factors nrf1 and nrf215,16(NFE2L1, NFE2L2), HERPUD1,17and chop/gadd153 (DDIT3).18 These downstream outputs of ATF4 either combat the effects of the stressors (eg, by activating the glutathione defense system or protein folding or degradation networks) or activate apoptotic death programmes if the stress is insurmountable (see for a more detailed summary).

NFE2L2 controls the expression of many enzymes related to the glutathione and quinone defense system. It also controls the transcription of several genes associated with bipolar disorder or schizophrenia including BDNFBS, CHGBS, GABRA1B, GABBR1S, GCLMS, GSTM1S, G6PDB, HMBSS, NQO2S, and SYN2S.8 HERPUD1 controls endoplasmic reticulum calcium homoeostasis and mitochondrial function19 and also plays a role in the endoplasmic reticulum–associated degradation pathway (ERAD) that detects and remove misfolded or degraded proteins.20 Such proteins are transported back to the cytosol for degradation by the ubiquitin-proteasomal system.21 DDIT3 controls the expression of genes related to apoptosis, free radical control (SOD2S), cell proliferation, adhesion, and protein processing (proteasomal elements).22,23

This system is counterbalanced by the phosphoinositide kinase/AKTBS survival pathway, which is activated by growth factors24 and by low-level NMDA receptor activation.25 eIF2B is phosphorylated and inhibited by glycogen synthase kinase 3 beta (GSK3BB)26 and the inhibition of GSK3BB by activation of the growth factor/AKTBS cascade removes this repression, allowing an increase in translation initiation and protein synthesis, an end point of growth factor effect.

This signaling network, as well as being related to environmental factors influencing the risk of psychiatric disease, is riddled with bipolar or schizophrenia-associated polymorphic genes whose products form components of these pathways, interact with, or are controlled by its component elements. This is illustrated in figure 1 and table 1.

Components of growth factor phosphoinositide-related signaling pathways include growth factors, cytokines, and tyrosine kinase receptors BDNFBS, CNTFS, EGFS, GFRA1S, IL10S, IL10RAS, NTF3S, NRG1BS, NRG3S, and ERBB4S, many of which are involved in the control of oligodendrocyte growth and development, inter alia. All these stimulate the phosphoinositide kinase/AKT1BS survival pathway, as do CHI3L1S, NCAM1BS, and P2RX7B. The phosphoinositide kinase-signaling network is represented by PIK3C3BS, PIK4CAB, PIP5K2ABS, PLCG1B, SYNJ1B, AKT1BS, GSK3BB, IMPA2BS, and TCF4B. The protein products of other susceptibility genes (BCRB, DUSP6B, FATB, GNAZB, PPP2R2CB, RGS4BS) bind to components of this pathway. Others bind to or are activated by phosphoinositol-phosphate derivatives of its components (HIP1RB, KCNQ2B, WFS1B) or are downstream targets of phosphorylation by GSK3BB (DPYSL2BS, KCNQ2B, TIMELESSBS) or AKT1BS (GSK3BB, NOS3B) or of the transcription factor TCF4B (THBS) (see Web site for details).

Bipolar disorder has been associated with a number of genes involved in protein sorting (NAPGB, HIP1RB, SYBL1B), glycosylation (ALG9B), or endoplasmic reticulum calcium homoeostasis (WFS1B). Defects in these processes lead to endoplasmic reticulum stress and activation of the unfolded protein response.27 HSPA5B and XBP1BS play a key role in the coordination of these pathways.28,29

The endoplasmic reticulum stress pathway is also activated by oxidative stress10 or by homocysteine,30 and oxidative stress pathways also lead into the eIF2-alpha pathway via the heme responsive kinase HRI (EIF2AK1). Elevated serum homocysteine levels have been observed in both bipolar disorder and schizophrenia,31 and a crucial gene involved in folate and homocysteine metabolism has been described as a common risk factor (MTHFRBS). Oxidative stress has been implicated in both bipolar disorder32and schizophrenia,8 and a number of related genes have been associated with either (G6PDB, NOS3B, GCLMS, GSTM1S, NQO2S, PTGS2S, S100BS, SLC1A2S, SOD2S, TYRS, TP53S, UCP2S, UCP4S) or both conditions (COMTBS, NOS1BS, ND4BS, NDUFV2BS).

Circadian Genes and the Control of Protein Synthesis

The processes regulated by these pathways are under circadian control in the brain. During periods of wakefulness, genes related to plasticity acquisition and potentiation, including BDNFBS, are upregulated as are the glutamate-related genes GRIN2ABS, genes related to mitochondrial energy metabolism, and genes related to the stress response (CHOP, PERK, and molecular chaperones, including HSPA5B). During sleep, genes involved in plasticity consolidation, membrane trafficking, cholesterol biosynthesis (a key process in myelination), protein translation, and GABAergic transmission are switched on. In global terms, protein translation and synthesis, the fulcrum of the growth factor and stress-activated pathways, appears to be switched off during wakefulness and turned on during sleep.33,34 The circadian genes associated with schizophrenia or bipolar disorder (PER3BS, TIMELESSBS, CLOCKBS, ARNTLB) may thus also feed into this signaling network although the point of control remains to be determined.

NMDA Receptors, Glutathione, and oligodendrocytes

Both schizophrenia and bipolar disorder have also been associated with a number of genes related to glutamatergic and in particular NMDA receptor signaling, (DAOBS, DAOABS, GRIN1BS, GRIN2ABS, GRIN2BBS, GRIN2DS, PPP3CCS, NOS1BS, NOSIAPBS). NMDA receptor activation phosphorylates and activates AKT1BS in neurones, and this effect can be related to the survival-promoting effects of low-level NMDA receptor activation.25,35 While NMDA receptors exist on oligodendrocytes,36 their ability to activate this pathway or their potential cytoprotective effect have not been examined in this cell type. The purinergic receptor P2RX7B has been shown to activate the AKT1BS pathway in astrocytes.37 It remains to be seen whether NMDA receptor activation affects protein translation in oligodendrocytes.

One of the key outputs of the ATF4 cascade is the control of glutathione-related defense mechanisms. Oligodendrocytes are particularly sensitive to the toxic effects of glutathione depletion,38 and the control of glutathione-related processes by this network may provide an additional means of dictating oligodendrocyte vulnerability in response to these types of stress. A number of schizophrenia susceptibility genes are related to the glutathione/quinone defense system (COMTBS, GCLMS, GSTM1S, NQO2S, SLC1A2S), while G6PDB is responsible for the regeneration of reduced glutathione following its oxidation.39 As NMDA receptor activation increases the release of the reduced form of glutathione, the proposed hypofunction of this glutamatergic signaling network in adulthood might also influence the ability of oligodendrocytes to cope with these types of stress.8 A number of genes associated with schizophrenia or bipolar disorder (AGAS, CNPS, MAGS, MLC1BS, MOGS, NOTCH4S, NRG1BS, OLIG2S, PAX6S, PLP1S, QK1S) are specifically concerned with oligodendrocyte function while others dictate oligodendrocyte viability in some way (see table 1). These factors may provide additional means of influencing oligodendrocyte function.


DISC1BS, which is localized in both neurons and white matter,40 appears to occupy a privileged position as a transduction hub within this network via its interaction with ATF4 and ATF5. Other binding partners of DISC1BS include the phosphatase TENC1,41 a negative regulator of PI3K/AKTBS signaling and an inhibitor of cell survival and proliferation.42 DISC1 also binds to the citron kinase CITB43 that is also associated with the NMDA receptor subunit GRIN1BS44 as well as to a number of other glutamate receptor scaffold proteins (AKAP9, ACTN2, GRIPAP1, HAPIP, SPTAN1)41 that are associated with GRIN1BS, GRIN2ABS, or GRIN2BBS.8 DISC1BS also binds to N-acetylglucosaminyltransferase III (GlcNAc-TIII) (MGAT3),41 an enzyme in the same glycosylation pathway as ALG9B (see Kegg pathway: DISC1BS has also been shown to bind to the eukaryotic translation initiation factor 3 (EIF3S3).45 Translation initiation factor 3 (eIF3) is a multisubunit complex containing at least 12 subunits, including EIF3S3. It binds to the 40S ribosomal subunit, promotes the binding of methionyl-tRNAi and mRNA, and interacts with several other initiation factors to form the 40S initiation complex.46 The overexpression of DISC1 results in the formation of cytoplasmic stress granules.45 These stress granules are observed in response to the diverse cellular stresses leading to eIF2-alpha phosphorylation.47 DISC1 also binds to the protein products of several other genes implicated in schizophrenia or bipolar disorder including DPYSL2BS, FEZ1S, NDE1S, MLC1S, and PDE4BBS (see Web site) and would thus appear to be an extremely important hub gene interacting with a variety of networks implicated in psychiatric disorders.

Environmental Stressors and Oligodendrocytes

The convergence of these signaling networks on a translation initiation factor (eIF2B) that, for unknown reasons, plays an important role in oligodendrocyte viability, only indirectly supports a role for this network in dictating the fate of these cells in bipolar disorder and schizophrenia. Other evidence suggests that the type of stressors associated with these diseases appear to target this cell type. Hypomyelination, in vivo, can be induced by prolonged postnatal starvation,48 the measles rubella virus,49 which is also able to kill oligodendrocytes in culture,50 or by herpes simplex.51 The Borrelia burgdorferi pathogen (responsible for lyme disease carried by the Ixodes tick) also appears to selectively target oligodendroglial cells.52

All cell types are sensitive to oxidative stress, but oligodendrocyte progenitors and developing oligodendrocytes in premature infants appear to be particularly sensitive to this type of stressor.53 Developing oligodendrocytes are also particularly sensitive to glutathione depletion,38 a situation observed in the frontal cortex in schizophrenia.54 Thus, a number of environmental stressors that may predispose to psychiatric disorders do appear to exert toxic effects on this cell population.

In vanishing white matter disease, environmental stressors (fright, fever, or minor head trauma) also markedly affect the progession of the disease, resulting in rapid neurological deterioration,55 suggesting that when eIF2B activity is compromised, there may be maladaptive responses to stress. Indeed, defects in eIF2B in vanishing white matter disease result in an increased stress response (ATF4 induction) in fibroblasts in response to endoplasmic reticulum stress.56 The increase in eIF2-alpha phosphorylation produced by heat shock is also decreased in lymphocyte cell lines isolated from these patients,57 and the unfolded protein response (PERK, CHOP, ATF4) is activated in both astrocytes and oligodendrocytes in postmortem brain tissue.58 These observations suggest that eIF2B malfunction must somehow control elements of the eIF2-alpha–signaling network, as well as protein translation, although how this is achieved remains to be determined.

Risk Factors in Adulthood

In both bipolar disorder and schizophrenia, the environmental stressors associated with disease occur early in life, many years before the development of the disease in adulthood. The age-at-onset for psychosis in schizophrenia correlates, in men and women, with the onset of puberty and in women with the menopause suggesting that sex-steroidal hormonal influences may also be involved in the later etiology of the disease.59 The progression of bipolar disorder has also been related to postpartum and menopausal events.60,61 Hormonal influences, particularly the hypothalamic-pituitary-adrenal stress axis also exert an influence on the development of bipolar disorder in adulthood.62 Many of these hormonal influences also affect oligodendrocyte function. For example, testosterone amplifies,63 while 17-beta oestradiol64 attenuates cytotoxin-induced oligodendrocyte cell death in vitro. Progesterone also promotes myelination in the peripheral and central nervous system.65 In adult rats, the prolonged administration of corticosterone has been shown to inhibit the proliferation of oligodendrocyte progenitors.66 Adrenaline, noradrenaline, and dopamine all exert toxic effects on oligodendrocytes, and these effects are accompanied by a reduction in glutathione levels and prevented by the hydrogen peroxide metabolizing enzyme, catalase, or by the glutathione precursor N-acetylcysteine.67,68 In adults, Interferon therapy has been associated with bipolar symptoms and psychiatric disturbances.69 Interferon alpha and beta can promote remyelination acutely but can exert toxic effects on oligodendrocytes in murine models of multiple sclerosis,70 while interferon gamma,71 TNFBS72 and IL1BBS,73 can all exert toxic effects on this cell type. Each of these activates the eIF2-alpha kinase PKR (EIF2AK2).

Thus, hormonal influences, stressors in adulthood, or other compromised signaling networks may also target oligodendrocyte viability in some way, as might further bouts of infection resulting in the production of cytotoxic cytokines (TNFBS, IL1BBS). These effects may be particularly deleterious if these cells have been somehow weakened by earlier events. Hormones and cytokines may well affect many other processes implicated in schizophrenia and bipolar disorder, but their ability to modify oligodendrocyte function represents a common area of overlap that merits further consideration.

Protein Synthesis and Synaptic Plasticity

Increased protein synthesis is necessary for the plastic changes associated with LTP,74 mediated by NMDA receptors (GRIN2ABS, GRIN2BBS, GRIN2DS). The eIF2-alpha kinase pathway is also involved in LTP, and a number of members of the translation initiation complex as well as translation elongation factors are localized within the postsynaptic density, suggesting that the apparatus necessary for dendritic protein synthesis is locally available.75 LTP decreases eIF2-alpha phosphorylation, allowing this increase in protein synthesis.76 Conversely, long-term depression, mediated by metabotropic glutamate receptors (GRM3BS, GRM5S), increases eIF2-alpha phosphorylation.77 eIF2-alpha phosphorylation activates ATF4, a repressor of LTP.78 Hippocampal LTP is also markedly attenuated by knockout of the eIF2-alpha kinase GCN2 (EIF2AK4).79 Many of the genes implicated in schizophrenia, including NMDA receptors and growth factors, can be linked to a signaling cascade implicated in the phenomenon of LTP.8 Thus, this protein translation signaling network may serve a dual function in regulating 2 aspects of schizophrenia pathology, synaptic plasticity, and oligodendrocyte viability.

Evidence for Disruption of These Pathways in Schizophrenia and Bipolar Disorder

The Stanley Medical Research Institute has published an online database containing the results of a number of microarray studies of bipolar disorder, schizophrenia, and depression. Contributors to these studies included the groups of C. A. Altar, S. Bahn, H. Chen, S. E. Dobrin, A. Fienberg, T. Kato, P. Sklar, M. Vawter, L. T. Young, and M. Elashoff whose work is collectively referenced here80 and within the database (

Gene families from these data sets were classified, by this group, in relation to Gene Ontology biological processes and function and Kegg pathways. These data are summarized in table 2. While the overall profile differs for schizophrenia and bipolar disorder, a large proportion of the gene families commonly dysregulated in schizophrenia and bipolar disorder relate to processes concerned with cell growth, protein synthesis, transport, and degradation. Expression changes for genes involved in protein biosynthesis and phosphoinositide signaling were also heavily represented in a microarray study of biopsied olfactory neuroepithelium isolated from bipolar disorder patients.81 Many of these processes, including protein transport and degradation, heat-shock protein and chaperone activity, ubiqitinylation and proteasomal activity, and glutathione metabolism relate specifically to the various downstream transcription factor outputs of ATF4. For example, HERPUD1 is involved in protein processing and degradation, DDIT3 is involved in the control of protein processing, cell growth, apoptosis, and glutathione homoeostasis, while NFE2L1 and NFE2L2 regulate genes coding for glutathione biosynthesis, as well as the expression of a number of genes implicated in schizophrenia or bipolar disorder. XBP1BS is concerned with the regulation of heat-shock proteins and chaperones and with protein degradation mediated by the ERAD pathway (see Web site and above). Although each disease specifically affects other processes, a common area of overlap, in these gene expression studies, relates specifically to the outputs of this growth factor/stress-activated kinase pathway.

Table 2.
A summary of the Highest Ranked Gene Families Whose Expression Is Dysregulated in Microarray Studies of Bipolar Disorder and Schizophrenia

The reactivity of this network also appears to be affected in peripheral cells. Leukocytes respond to bacteria or viruses by increasing the production of interferons (an effect mediated by the eIF2-alpha kinase, PKR). This response is attenuated in leukocytes isolated from schizophrenic patients.82,83

Conclusion and Speculation

Identical twin studies have shown that the concordance rates in schizophrenia (48%)84 or bipolar disorder (40–70%)85 are less than 100%. Monozygotic twins share the same genome and there may thus be no universal causative gene for these disorders. Although many genes have been associated with these diseases, there is extreme disparity between the individual gene association results. While there is general agreement that DISC1 is a very important risk factor, carriers of the DISC1BS translocation can also be asymptomatic.86 Nevertheless, genes play an important role in modifying the risk of developing these diseases, even though each susceptibility variant may also exist in the normal population. Similarly, while famine, viral infection, or other stressors in early life have been reported to increase the risk of bipolar disorder and schizophrenia, clearly, not all individuals subject to these stresses develop these conditions. Thus, one could argue that neither genes, nor the environment, per se, cause psychiatric diseases.

However, the environmental risk factors activate a key stress-related pathway, composed of, regulated by, or regulating many of these susceptibility genes. Microarray experiments also suggest that the outputs of this network are disrupted in both these conditions. This pathway is important in dictating the vulnerability of oligodendrocytes and also plays a key role in long-term synaptic plasticity. Oligodendrocyte loss, hypomyelination, and altered synaptic plasticity are all components of the pathology of bipolar disorder and schizophrenia. In other polygenic diseases (eg, bladder cancer87), the degree of risk afforded by susceptibility genes is magnified by the presence of other polymorphic genes in the same signaling network. Similar integrative effects are likely to operate in schizophrenia and bipolar disorder (see Carter8 for discussion). Such effects might also be envisaged for gene-environment interactions, particularly when the signaling networks affected by the environment and the susceptibility genes so clearly overlap. Indeed, the association of APOEBS with schizophrenia in the Chinese population is influenced by dates of birth corresponding to periods of famine.88 In bipolar disorder, additive risk-promoting effects have also been observed between the COMTBS polymorphism and herpes simplex viral infection.89 The pathological effect of any particular gene variant may thus depend not only on the presence of other polymorphic genes in a particular pathway but also on the presence of environmental influences that may also compromise the same signaling network.

Because the environmental risk factors activate a pathway largely composed of susceptibility genes, there are compelling reasons to suggest that the environmental factors may in fact be causative but only in individuals where this stress-signaling network has been compromised by polymorphic susceptibility gene variants. This has important implications because certain of these causes are preventable or avoidable. For example, vaccination against rubella or influenza prior to pregnancy might be a simple but effective means of reducing the incidence of these psychiatric conditions, a possibility that does not seem to have been addressed in the medical literature. Oligodendrocyte cell loss may also be preventable, both during development and in adulthood. Glutathione (or its precursor N-acetylcysteine) in particular has been shown to protect these cells from a variety of toxic insults.8 N-acetylcysteine also prevents the oligodendrocyte cell loss in rat pups whose mothers were treated with lipopolysaccharide during gestation.90 The glutathione defense system is a major output of the growth factor/stress kinase-signaling network, and a means of targeting this system may well have beneficial effects in both bipolar disorder and schizophrenia.

Susceptibility gene variants are present from the moment of conception, while the stressors associated with these diseases occur early in life. If these combine to compromise eIF2b function, then the suggested downstream consequences of this effect, oligodendrocyte malfunction and modified synaptic plasticity, might be considered as early prime events in the pathology of both bipolar disorder and schizophrenia. It is thus worth considering whether oligodendrocyte dysfunction in early life is a precipitating factor responsible for other features of these disorders.

In mice or rats, maternal immune activation with the viral mimic and cytokine releaser polyriboinosinic-polyribocytidilic acid (POLY-IC) produces behavioral changes in the adult offspring. These include increased behavioral sensitivity to the NMDA antagonist MK-801, hyperactivity, and cognitive disturbances. Dopamine turnover is increased in the striatum and the behavioral effects were sensitive to neuroleptics.91,92 Although viral infection, which is modeled by POLY-IC, does target oligodendrocytes (see above), their role was not examined in these experiments. Interestingly, mice with combined knockout of fibroblast growth factor receptor (FGFR2) and the oligodendrocyte-specific cyclic nucleotide phosphodiesterase (CNP1S) display pronounced hyperactivity that is blocked by neuroleptics or tyrosine hydroxylase inhibition.93 Thus, it would appear that modifications in oligodendrocyte function are able to affect dopaminergic activity, the keystone of psychosis. While the role of oligodendrocytes in myelination has been extensively studied, their potential role in synaptic plasticity or neurotransmitter function has been relatively overlooked,94 a subject that merits further investigation.

In the clinical context, psychosis is common in other demyelinating diseases, eg, metachromatic leukodystrophy.95 Psychiatric symptoms mimicking those of bipolar disorder and schizophrenia are also prevalent in multiple sclerosis patients.96 Perhaps, a reclassification of bipolar disorder and schizophrenia as mild leukodystropies might be a useful conceptual framework for research.

Other genes (eg, those specific to either condition; see table 1 and Web site) signaling pathways and subpathologies are likely to be involved in distinguishing bipolar disorder and schizophrenia. However, the key role of the oligodendrocyte in both conditions merits closer attention, particularly in relation to future potential therapies and prevention. Nature and nurture both play a role in psychiatric disorders, although the weight of each has had its vigorous proponents and opponents.97 The signaling network described above suggests that both may impinge on a common signaling pathway, composed of psychiatric susceptibility genes (nature) and influenced by diverse environmental stressors (nurture). A convergence point of this system (eIF2B) appears to be specifically involved in determining oligodendrocyte viability, and further characterization of this network may help in our understanding of this particular sub-pathology of schizophrenia and bipolar disorder. Targeting this system may also lead to the development of radically different and effective treatment and prevention strategies.


1. Murray RM, Jones PB, Susser E, Van Os J, Cannon M (eds). The Epidemiology of Schizophrenia. Cambridge: Cambridge University Press, 2002; 470, ISBN: 0-521-77540-X.
2. Brown AS, Van Os J, Driessens C, Hoek HW, Susser ES. Further evidence of relation between prenatal famine and major affective disorder. Am J Psychiatry. 2000;157:190–195. [PubMed]
3. Yolken RH, Torrey EF. Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev. 1995;8:131–145. [PMC free article] [PubMed]
4. Uranova N, Orlovskaya D, Vikhreva O, et al. Electron microscopy of oligodendroglia in severe mental illness. Brain Res Bull. 2001;55:597–610. [PubMed]
5. Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI. Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res. 2004;67:269–275. [PubMed]
6. Chambers JS, Perrone-Bizzozero NI. Altered myelination of the hippocampal formation in subjects with schizophrenia and bipolar disorder. Neurochem Res. 2004;29:2293–2302. [PubMed]
7. McClellan JM, Susser E, King MC. Maternal famine, de novo mutations, and schizophrenia. JAMA. 2006;296:582–584. [PubMed]
8. Carter CJ. Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. Schizophr Res. 2006;86:1–14. [PubMed]
9. Pronk JC, van Kollenburg B, Scheper GC, van der Knaap MS. Vanishing white matter disease: a review with focus on its genetics. Ment Retard Dev Disabil Res Rev. 2006;12:123–128. [PubMed]
10. Cullinan SB, Diehl JA. Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol. 2005;38:317–332. [PubMed]
11. Pavitt GD. eIF2B, a mediator of general and gene-specific translational control. Biochem Soc Trans. 2005;33:1487–1492. [PubMed]
12. Proud CG. Regulation of eukaryotic initiation factor eIF2B. Prog Mol Subcell Biol. 2001;26:95–114. [PubMed]
13. Wek RC, Jiang HY, Anthony TG. Coping with stress: eIF2 kinases and translational control. Biochem SocTrans. 2006;34:7–11. [PubMed]
14. Harding HP, Zhang Y, Zeng H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11:619–633. [PubMed]
15. Murphy P, Kolsto A. Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development. Mech Dev. 2000;97:141–148. [PubMed]
16. He CH, Gong P, Hu B, et al. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem. 2001;276:20858–20865. [PubMed]
17. Ma Y, Hendershot LM. Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways. J Biol Chem. 2004;279:13792–13799. [PubMed]
18. Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ. Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J. 1999;339:135–141. [PubMed]
19. Chan SL, Fu W, Zhang P, et al. Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress. J Biol Chem. 2004;279:28733–28743. [PubMed]
20. Schulze A, Standera S, Buerger E, et al. The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway. J Mol Biol. 2005;354:1021–1027. [PubMed]
21. Kaneko M, Nomura Y. ER signaling in unfolded protein response. Life Sci. 2003;74:199–205. [PubMed]
22. You KR, Liu MJ, Han XJ, Lee ZW, Kim DG. Transcriptional regulation of the human transferrin gene by GADD153 in hepatoma cells. Hepatology. 2003;38:745–755. [PubMed]
23. Maytin EV, Ubeda M, Lin JC, Habener JF. Stress-inducible transcription factor CHOP/gadd153 induces apoptosis in mammalian cells via p38 kinase-dependent and -independent mechanisms. Exp Cell Res. 2001;267:193–204. [PubMed]
24. Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res. 1999;253:210–229. [PubMed]
25. Lafon-Cazal M, Perez V, Bockaert J, Marin P. Akt mediates the anti-apoptotic effect of NMDA but not that induced by potassium depolarization in cultured cerebellar granule cells. Eur J Neurosci. 2002;16:575–583. [PubMed]
26. Welsh GI, Miller CM, Loughlin AJ, Price NT, Proud CG. Regulation of eukaryotic initiation factor eIF2B: glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Lett. 1998;421:125–130. [PubMed]
27. Zhang K, Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology. 2006;66:S102–S109. [PubMed]
28. Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 2005;35:373–381. [PubMed]
29. Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003;23:7448–7459. [PMC free article] [PubMed]
30. Roybal CN, Yang S, Sun CW, et al. Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem. 2004;279:14844–14852. [PubMed]
31. Levine J, Sela BA, Osher Y, Belmaker RH. High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1181–1191. [PubMed]
32. Andreazza AC, Cassini C, Rosa AR, et al. Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res. 2006 [PubMed]
33. Cirelli C, Tononi G. Gene expression in the brain across the sleep-waking cycle. Brain Res. 2000;885:303–321. [PubMed]
34. Cirelli C, Gutierrez CM, Tononi G. Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron. 2004;41:35–43. [PubMed]
35. Sanchez-Perez AM, Llansola M, Felipo V. Modulation of NMDA receptors by AKT kinase. Neurochem Int. 2006;49:351–358. [PubMed]
36. Wong R. NMDA receptors expressed in oligodendrocytes. Bioessays. 2006;28:460–464. [PubMed]
37. Jacques-Silva MC, Rodnight R, Lenz G, et al. P2X7 receptors stimulate AKT phosphorylation in astrocytes. Br J Pharmacol. 2004;141:1106–1117. [PMC free article] [PubMed]
38. Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ. Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci. 1998;18:6241–6253. [PubMed]
39. Fujii H. Glucose-6-phosphate dehydrogenase. Nippon Rinsho. 1995;53:1221–1225. [PubMed]
40. Kirkpatrick B, Xu L, Cascella N, Ozeki Y, Sawa A, Roberts RC. DISC1 immunoreactivity at the light and ultrastructural level in the human neocortex. J Comp Neurol. 2006;497:436–450. [PubMed]
41. Millar JK, Christie S, Porteous DJ. Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun. 2003;311:1019–1025. [PubMed]
42. Hafizi S, Ibraimi F, Dahlback B. C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration. FASEB J. 2005;19:971–973. [PubMed]
43. Ozeki Y, Tomoda T, Kleiderlein J, et al. Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA. 2003;100:289–294. [PubMed]
44. Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci. 2000;3:661–669. [PubMed]
45. Ogawa F, Kasai M, Akiyama T. A functional link between Disrupted-In-Schizophrenia 1 and the eukaryotic translation initiation factor 3. Biochem Biophys ResCommun. 2005;338:771–776. [PubMed]
46. Mayeur GL, Fraser CS, Peiretti F, Block KL, Hershey JW. Characterization of eIF3k: a newly discovered subunit of mammalian translation initiation factor elF3. Eur J Biochem. 2003;270:4133–4139. [PubMed]
47. Anderson P, Kedersha N. Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation. Cell Stress Chaperones. 2002;7:213–221. [PMC free article] [PubMed]
48. Wiggins RC, Fuller GN. Early postnatal starvation causes lasting brain hypomyelination. J Neurochem. 1978;30:1231–1237. [PubMed]
49. Kemper TL, Lecours AR, Gates MJ, Yakovlev PI. Retardation of the myelo- and cytoarchitectonic maturation of the brain in the congenital rubella syndrome. Res Publ Assoc Res Nerv Ment Dis. 1973;51:23–62. [PubMed]
50. Domegan LM, Atkins GJ. Apoptosis induction by the Therien and vaccine RA27/3 strains of rubella virus causes depletion of oligodendrocytes from rat neural cell cultures. J Gen Virol. 2002;83:2135–2143. [PubMed]
51. Kastrukoff LF, Lau AS, Kim SU. Multifocal CNS demyelination following peripheral inoculation with herpes simplex virus type 1. Ann Neurol. 1987;22:52–59. [PubMed]
52. Garcia-Monco JC, Fernandez Villar B, Szczepanski A, Benach JL. Cytotoxicity of Borrelia burgdorferi for cultured rat glial cells. J Infect Dis. 1991;163:1362–1366. [PubMed]
53. Blomgren K, Hagberg H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med. 2006;40:388–397. [PubMed]
54. Do KQ, Trabesinger AH, Kirsten-Kruger M, et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000;12:3721–3728. [PubMed]
55. van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol. 2006;5:413–423. [PubMed]
56. Kantor L, Harding HP, Ron D, et al. Heightened stress response in primary fibroblasts expressing mutant eIF2B genes from CACH/VWM leukodystrophy patients. Hum Genet. 2005;118:99–106. [PubMed]
57. van Kollenburg B, Thomas AA, Vermeulen G, et al. Regulation of protein synthesis in lymphoblasts from vanishing white matter patients. Neurobiol Dis. 2006;21:496–504. [PubMed]
58. van Kollenburg B, van Dijk J, Garbern J, et al. Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease. J Neuropathol Exp Neurol. 2006;65:707–715. [PubMed]
59. Stevens JR. Schizophrenia: reproductive hormones and the brain. Am J Psychiatry. 2002;159:713–719. [PubMed]
60. Sajatovic M, Rosenthal MB, Plax MS, Meyer ML, Bingham CR. Mental illness and menopause: a patient and family perspective. J Gend Specif Med. 2003;6:31–34. [PubMed]
61. Blehar MC, DePaulo JR, Jr, Gershon ES, Reich T, Simpson SG, Nurnberger JI., Jr Women with bipolar disorder: findings from the NIMH Genetics Initiative sample. Psychopharmacol Bull. 1998;34:239–243. [PubMed]
62. Daban C, Vieta E, Mackin P, Young AH. Hypothalamic-pituitary-adrenal axis and bipolar disorder. Psychiatr Clin North Am. 2005;28:469–480. [PubMed]
63. Caruso A, Di Giorgi Gerevini V, Castiglione M, et al. Testosterone amplifies excitotoxic damage of cultured oligodendrocytes. J Neurochem. 2004;88:1179–1185. [PubMed]
64. Takao T, Flint N, Lee L, Ying X, Merrill J, Chandross KJ. 17beta-estradiol protects oligodendrocytes from cytotoxicity induced cell death. J Neurochem. 2004;89:660–673. [PubMed]
65. Schumacher M, Guennoun R, Robert F, et al. Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination. Growth Horm IGF Res. 2004;14(Suppl A):S18–S33. [PubMed]
66. Alonso G. Prolonged corticosterone treatment of adult rats inhibits the proliferation of oligodendrocyte progenitors present throughout white and gray matter regions of the brain. Glia. 2000;31:219–231. [PubMed]
67. Khorchid A, Fragoso G, Shore G, Almazan G. Catecholamine-induced oligodendrocyte cell death in culture is developmentally regulated and involves free radical generation and differential activation of caspase-3. Glia. 2002;40:283–299. [PubMed]
68. Noble PG, Antel JP, Yong VW. Astrocytes and catalase prevent the toxicity of catecholamines to oligodendrocytes. Brain Res. 1994;633:83–90. [PubMed]
69. Greenberg DB, Jonasch E, Gadd MA, et al. Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes. Cancer. 2000;89:356–362. [PubMed]
70. Njenga MK, Coenen MJ, DeCuir N, Yeh HY, Rodriguez M. Short-term treatment with interferon-alpha/beta promotes remyelination, whereas long-term treatment aggravates demyelination in a murine model of multiple sclerosis. J Neurosci Res. 2000;59:661–670. [PubMed]
71. Popko B, Baerwald KD. Oligodendroglial response to the immune cytokine interferon gamma. Neurochem Res. 1999;24:331–338. [PubMed]
72. Cammer W. Protection of cultured oligodendrocytes against tumor necrosis factor-alpha by the antioxidants coenzyme Q(10) and N-acetyl cysteine. Brain Res Bull. 2002;58:587–592. [PubMed]
73. Takahashi JL, Giuliani F, Power C, Imai Y, Yong VW. Interleukin-1beta promotes oligodendrocyte death through glutamate excitotoxicity. Ann Neurol. 2003;53:588–595. [PubMed]
74. Pfeiffer BE, Huber KM. Current advances in local protein synthesis and synaptic plasticity. J Neurosci. 2006;26:7147–7150. [PubMed]
75. Pocklington AJ, Cumiskey M, Armstrong JD, Grant SG The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour. Mol Syst Biol. 2006;2:2006. [PMC free article] [PubMed]
76. Costa-Mattioli M, Gobert D, Stern E, et al. Translational control of synaptic plasticity and memory by the eIF2a signaling pathway. Soc Neurosci. 2006:632–16.
77. Hou S, Antoine M, Hoeffer C, et al. Translation initiation factor eIF2a phosphorylation during mGluR-LTD and L-LTP in hippocampal area CA1. Soc Neurosci. 2006:750–19.
78. Chen A, Muzzio IA, Malleret G, et al. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron. 2003;39:655–669. [PubMed]
79. Costa-Mattioli M, Gobert D, Harding H, et al. Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature. 2005;436:1166–1173. [PMC free article] [PubMed]
80. Higgs BW, Elashoff M, Richman S, Barci B. An online database for brain disease research. BMC Genomics. 2006;7:70. [PMC free article] [PubMed]
81. McCurdy RD, Feron F, Perry C, et al. Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses. Schizophr Res. 2006;82:163–173. [PubMed]
82. Moises HW, Schindler L, Leroux M, Kirchner H. Decreased production of interferon alpha and interferon gamma in leucocyte cultures of schizophrenic patients. Acta Psychiatr Scand. 1985;72:45–50. [PubMed]
83. Katila H, Cantell K, Hirvonen S, Rimon R. Production of interferon-alpha and gamma by leukocytes from patients with schizophrenia. Schizophr Res. 1989;2:361–365. [PubMed]
84. Gottesman I. Schizophrenia Genesis: The Origins of Madness. New York, NY: Freeman; 1991.
85. Craddock N, Jones I. Genetics of bipolar disorder. J Med Genet. 1999;36:585–594. [PMC free article] [PubMed]
86. Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders–cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 2001;69:428–433. [PubMed]
87. Wu X, Gu J, Grossman HB, et al. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am J Hum Genet. 2006;78:464–479. [PubMed]
88. Liu W, Breen G, Zhang J, et al. Association of APOE gene with schizophrenia in Chinese: a possible risk factor in times of malnutrition. Schizophr Res. 2003;62:225–230. [PubMed]
89. Dickerson FB, Boronow JJ, Stallings C, et al. The catechol O-methyltransferase Val158Met polymorphism and herpes simplex virus type 1 infection are risk factors for cognitive impairment in bipolar disorder: additive gene-environmental effects in a complex human psychiatric disorder. Bipolar Disord. 2006;8:124–132. [PubMed]
90. Paintlia MK, Paintlia AS, Barbosa E, Singh I, Singh AK. N-acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain. J Neurosci Res. 2004;78:347–361. [PubMed]
91. Zuckerman L, Weiner I. Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. J Psychiatr Res. 2005;39:311–323. [PubMed]
92. Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry. 2006;59:546–554. [PubMed]
93. Kaga Y, Shoemaker WJ, Furusho M, et al. Mice with conditional inactivation of fibroblast growth factor receptor-2 signaling in oligodendrocytes have normal myelin but display dramatic hyperactivity when combined with Cnp1 inactivation. J Neurosci. 2006;26:12339–12350. [PubMed]
94. Fields RD. Myelination: an overlooked mechanism of synaptic plasticity? Neuroscientist. 2005;11:528–531. [PMC free article] [PubMed]
95. Hyde TM. Ziegler JC, Weinberger DR. Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch Neurol. 1992;49:401–406. [PubMed]
96. Feinstein A. The neuropsychiatry of multiple sclerosis. Can J Psychiatry. 2004;49:157–163. [PubMed]
97. Tsuang MT, Bar JL, Stone WS, Faraone SV. Gene-environment interactions in mental disorders. World Psychiatry. 2004;3:73–83. [PubMed]

Articles from Schizophrenia Bulletin are provided here courtesy of Oxford University Press