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 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.