Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia. However, the inheritance of a single major gene does not serve as a vulnerability determinant. Instead, the accumulation of heterogeneous, multiple genetic abnormalities, each with a small effect, contribute to an increased risk of disease in carriers. Genome- wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Although GWASs have identified promising candidate genes for schizophrenia, they have limited genetic effects and no single proposed gene is sufficient to cause the disease. Therefore, identification of specific pathways will provide the cue to understand the genetic architecture of the disease. Recently, we performed GWAS of schizophrenia in Japanese population for searching schizophrenia susceptibility genes. In this study, using the data, we focused on a group of genes to examine whether a subset of genes categorized into some signaling pathway are involved in the pathogeneses of disease, beyond single genes. We unveiled the accumulation of association signals from genes of GABAergic pathway in schizophrenia. The GABAergic signaling cascade plays a critical role in the regulation of a diverse array of neuronal functions relevant to the pathogenesis of schizophrenia. These results do provide useful clues to unravel the complicated pathophysiology of schizophrenia.

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Genes are major contributors to schizophrenia. Studies aiming to identify susceptibility genes for schizophrenia are faced with the confounds of subjective clinical criteria, commonly occurring phenocopies, significant between-subject variability of candidate traits, and the likelihood of allelic and locus heterogeneity. The intermediate phenotype concept represents a strategy for identifying risk genes for schizophrenia and for characterizing the neural systems affected by risk gene variants to elucidate quantitative, mechanistic aspects of brain function implicated in schizophrenia. Intermediate phenotypes are defined by being heritable, being able to measure quantitatively ; being related to the disorder and its symptoms in the general population ; being stable over time ; showing increased expression in unaffected relatives of probands ; and cosegregation with the disorder in families. Intermediate phenotypes in schizophrenia are neurocognition, neuroimaging, neurophysiology, etc. Progress in the identification of meaningful intermediate phenotypes in schizophrenia has been made by the advance of newer methods in cognitive neuroscience and neuroimaging, and the use of combined multimodal techniques. In this review, we present concept, recent work, and future perspective of intermediate phenotype.

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Mutations of the FMR1 (fragile X mental retardation 1) gene produce a diverse range of clinical and behavioral pheno-types.Expansions of the CGG repeat over 200 result in the deficiency of FMRP that underlies the fragile X syndrome (FXS). CGG repeat expansions in the premutation range (55-200 CGGs) are associated with different types of clinical phenotypes including the fragile X-related tremor and ataxia syndrome (FXTAS), a late onset neurodegenerative disorder primarily affecting older male premutation careers. Although its molecular mechanism is still unclear, a hypothesis of mRNA-gain-of-function has been proposed, which proposes that abnormally elevated levels of FMR1 mRNA are responsible for degenerative processes affecting the FXTAS brain. Here we review recent findings of patients with FXTAS and unaffected premutation careers using multiple MRI modalities including the high-resolution structural MRI, functional MRI, and diffusion tensor imaging (DTI) to bridge the gap between molecular biological processes and their clinical manifestations. These studies revealed patterns of abnormalities characteristic to FXTAS, some of which were identified in the milder form among unaffected premutation careers. In addition, the studies found several MRI measures that are correlated with molecular variables of FMR1, including the CGG repeat number and the levels of mRNA and FMRP. These findings indicate that the brain imaging studies of FMR1 premutation provide unique opportunities to investigate the relationships of the molecular mechanisms, neural systems, and clinical observations.

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Several researchers have discovered monozygotic twins that are discordant for several phenotypes caused by genomic differences. Recently, copy number variations (CNVs) have gained attention as common structural variations in the human genome that strongly affect genomic diversity. CNVs can play a role in the development of several diseases including neuropsychiatric disorders, particularly autism spectrum disorder and schizophrenia. Recent reports have indicated that monozygotic twins can show different CNV profiles. As a trial to identify susceptible loci for schizophrenia, we searched for CNVs in three pairs of monozygotic twins discordant for schizophrenia using the Affymetrix Genome-Wide Human SNP Array 6. 0. A paired analysis of copy number state detected several deleted or amplificated regions in the twins’ genomes. However, the differences between twin pairs could not be confirmed in any of the tested regions using quantitative PCR. Although we did not find any differences in copy numbers between the twin pairs in this study, CNV analysis of discordant monozygotic twin is still likely to be a powerful tool for identifying the loci responsible for schizophrenia.

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Complex interaction of genetic and environmental factors is believed to cause psychiatric disorders. Despite the extensive efforts, the genetic factors of psychiatric disorders are still not known. Recently, it has been reported that genomic DNA derived from brain tissue contain quantitative and qualitative differences. For example, epigenetic modification of cytosine residue is considered as a qualitative difference, and copy number variations, chromosomal aneuploidy, and dynamics of retrotransposon are considered as the quantitative differences. We discuss about the recent studies about these variations in brain genome and their possible association with psychiatric disorders.

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Recent reports have suggested that epigenetic gene regulations are closely associated with the development of stress vulnerability, and also contribute to behavioral responses to chronic stress and antidepressants. There are evidences suggesting that histone deacetylase (HDAC) inhibitors have modest antidepressant-like effects in rodents. However, molecular mechanisms of antidepressant actions induced by HDAC inhibitors remain unclear. The purpose of this study is to clarify molecular mechanisms of antidepressant actions by HDAC inhibitors. First, we confirmed the rapid antidepressant effect of a HDAC inhibitor, SAHA using the model mouse for depression. We found that subchronic treatment with SAHA reversed the increased depression-related behaviors in mice subjected to chronic ultra mild stress. In addition, subchronic treatment with SAHA enhanced the expression of calcium/calmodulin-dependent protein kinase (CaMK) IIß mRNA in the hippocampus of stressed mice. However, subchronic treatment with imipramine did not affect the expression of CaMKIIß, as well as depression-related behaviors in stressed mice. These data suggest that SAHA has a rapid antidepressant action, and that the induction of CaMKIIß in the hippocampus by SAHA may contribute to the antidepressant action. Furthermore, we found the modest induction of CaMKIIß mRNA by HDAC inhibitors in the neuroblastoma Neuro 2a cells. Also, the number of differentiated cells was significantly increased by HDAC inhibitors. Importantly, the induction of cell differentiation by HDAC inhibitors was blocked by treatment with CaMKII inhibitors and CaMKIIß knockdown. Thus, our data suggest that the induction of CaMKIIß by HDAC inhibitors in the hippocampus might be involved in the structural plasticity and the subsequent antidepressant action.

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[in Japanese]

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Evolutionary psychology is an approach to psychology, in which knowledge and principles from evolutionary biology are put to use in research on the structure of the human mind. By applying evolutionary psychology to an understanding of mental disorder, examination of the ultimate factors why its condition and the features have arisen is attained. This article reviews several important evolutionary explanations of eating disorders, particularly anorexia nervosa (AN), and discusses the possibility of understanding the psychopathology and development of new treatments for eating disor-ders based on evolutionary psychology and evolutionary psychiatry. Three major hypotheses : “the reproductive suppression hypothesis”, “the sexual competition hypothesis”, and “the flee from famine hypothesis” are explained. These evolutionary hypotheses are difficult to confirm, but at least they succeed, to some extent, in accounting for the unusual mix of features found in AN that are otherwise resistant to explanation. For example, long term dietary restriction, female preponderance, hyperactivity despite severe emaciation, and body image distortion. The importance of evolutionary theory to future understanding, and development of new treatments for eating disorders is outlined.

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[in Japanese]

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[in Japanese]

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Cortical thinning in schizophrenia is thought to reflect the key pathophysiology such as reduced neuropil density 7). Although the effects of aging on the cortical morphometry of the disease have been researched for many years, decisive conclusion has yet to been reached 1, 3, 8, 12, 16, 17, 18). This section reviews aging influence on cortical thickness in schizophrenia, to examine if such influence shows separate pathological process compared to healthy controls. We also introduce our recent study of cortical thickness on the disease, applying surface- based analysis 10). Patients with schizophrenia exhibited both global and regional cortical thinning, in multiple regions including the prefrontal and temporal cortices. The correlation between age and cortical thickness showed a similar pattern between patients and controls. These results suggest that the cortical thinning in schizophrenia might not be progressive over the course of the illness, and may reflect pathological processes occurring in a relatively limited period prior to or around the onset of illness.

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