Epigenetics and Psychiatry

Psychiatric disorders including major depressive disorder, drug addiction, and schizophrenia are debilitating illnesses with a multitude of complex symptoms underlying each of these disorders. In recent years, it has become appreciated that the onset and development of these disorders goes beyond the one gene–one disease approach. Rather, the involvement of many genes is likely linked to these illnesses, and regulating the activation or silencing of gene function may play a crucial role in contributing to their pathophysiology. Epigenetic modifications such as histone acetylation and deacetylation, as well as DNA methylation can induce lasting and stable changes in gene expression, and have therefore been implicated in promoting the adaptive behavioral and neuronal changes that accompany each of these illnesses. In this review we will discuss some of the latest work implicating a potential role for epigenetics in psychiatric disorders, namely, depression, addiction, and schizophrenia as well as a possible role in treatment.     

Microarray screening of lymphocyte gene expression differences in a multiplex schizophrenia pedigree

In order to help prioritize the selection of candidate genes and to study possible trait and not state related changes in gene expression, we compared lymphocytic gene expression patterns of five individual family members with schizophrenia and nine unaffected individuals from a large multiplex high density pedigree. We screened gene expression by microarray consisting of 1128 brain focused genes. Three criteria for selection of microarray gene differences between schizophrenia and unaffected family members were employed: a significant t-test, expression in a majority of subjects, and fold change magnitude. Gene expression levels were significantly different for nine genes between individuals with schizophrenia compared to unaffected controls, and two genes were validated by real-time PCR. The expression of the neuropeptide Y receptor Y1 gene (NPY1R localized at 4q31.3-q32) and the human guanine nucleotide-binding regulatory protein Go-alpha (GNAO1 localized at 16q13) was significantly decreased in individuals with schizophrenia compared to unaffected family controls by microarray and real-time PCR. The cytosolic malate dehydrogenase gene (MDH1 localized at 2p13.3) was also significantly increased by microarray analysis and showed a trend for increase by real-time PCR. The significant genes are discussed in terms of proximity to linkage regions, prior association studies of schizophrenia, and other reports of microarray screening of schizophrenia tissue. Evidence from these studies taken together with the present study suggests critical pathways in schizophrenia may be studied in peripheral tissue as part of the strategy in functional genomic convergence. This preliminary study needs to be repeated by screening a larger set of genes in additional families with schizophrenia. The present study offers support for examination of gene expression patterns using lymphocytic RNA for complex neuropsychiatric disorders from large cohorts of patients.     

An agenda for psychiatric genetics.

Although it has long been known that people inherit vulnerabilities to particular forms of mental illness, ongoing advances in psychiatric genetics and DNA technology are only now making it possible to actually find the specific genes and gene variants that play critical roles in complex disorders, such as schizophrenia and bipolar disorder. For this reason, the National Institute of Mental Health convened a work group "to facilitate the search for the genes that influence mental disorders"--genes whose identification will affect diagnosis, prevention, and treatment. This article briefly summarizes the problems addressed by the work group and its main recommendations.     

Correlation analysis between genome-wide expression profiles and cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders

Cytoarchitectural abnormalities have been described in the prefrontal cortex of subjects with schizophrenia, bipolar disorder and depression. However, little is known about the gene expression profiles associated with these abnormalities. Genome-wide expression profiling technology provides an unbiased approach to identifying candidate genes and biological processes that may be associated with complex biological traits such as cytoarchitecture. In this study, we explored expression profiles associated with the abnormalities by using publicly available microarray metadata and cytoarchitectural data from post-mortem samples of the frontal cortex from 54 subjects (schizophrenia, n=14; bipolar disorder, n=13; depression, n=12 and controls n=15). Correlation analysis between genome-wide expression levels and cytoarchitectural traits revealed that 818 genes were significantly correlated with a decrease in the number of perineuronal oligodendrocytes across all subjects. A total of 600 genes were significantly correlated with a decrease in density of calbindin-positive interneurons across all subjects. Multiple biological processes including cellular metabolism, central nervous system development, cell motility and programmed cell death were significantly overrepresented in both correlated gene lists. These findings may provide novel insights into the molecular mechanisms that underlie the cytoarchitectural abnormalities of perineuronal oligodendrocytes and calbindin-containing GABAergic interneurons in the prefrontal cortex of the major psychiatric disorders.     

Expression of Kruppel-like factor 5 gene in human brain and association of the gene with the susceptibility to schizophrenia

Genome-wide gene expression analysis using DNA microarray technology is a potential tool to search for unexpected genes that have a susceptibility to schizophrenia. We carried out a microarray analysis in the postmortem prefrontal cortex and found that the expression of the KLF5 gene, whose locus is on 13q21, was down-regulated in schizophrenia patients. This result was confirmed by a Western blot analysis. In a genetic study, we found that a polymorphism of the KLF5 gene (− 1593T>C) was associated with schizophrenia. We identified neurons in the prefrontal cortex of human brain as sites of KLF5 expression by in situ hybridization and immunohistochemistry. KLF5 was immunohistochemically localized in granular and pyramidal cells in the hippocampus, which are the principal source of glutamatergic neurotransmission. These findings suggest that the KLF5 gene is a novel schizophrenia-susceptibility gene, and that the expression of the gene is involved in the pathophysiology of schizophrenia via glutamatergic neurotransmission.     

Epigenetics and Psychiatry

Psychiatric disorders including major depressive disorder, drug addiction, and schizophrenia are debilitating illnesses with a multitude of complex symptoms underlying each of these disorders. In recent years, it has become appreciated that the onset and development of these disorders goes beyond the one gene–one disease approach. Rather, the involvement of many genes is likely linked to these illnesses, and regulating the activation or silencing of gene function may play a crucial role in contributing to their pathophysiology. Epigenetic modifications such as histone acetylation and deacetylation, as well as DNA methylation can induce lasting and stable changes in gene expression, and have therefore been implicated in promoting the adaptive behavioral and neuronal changes that accompany each of these illnesses. In this review we will discuss some of the latest work implicating a potential role for epigenetics in psychiatric disorders, namely, depression, addiction, and schizophrenia as well as a possible role in treatment.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-013-0213-6) contains supplementary material, which is available to authorized users.     

DNA microarrays: translation of the genome from laboratory to clinic

As the complete sequences of human and other mammalian genomes become available we are faced with the challenge of understanding how variation in sequence and gene expression contributes to neurological and psychiatric disorders. DNA microarrays, or DNA chips, provide the means to measure simultaneously where and when thousands of genes are expressed. Microarrays are changing the way that researchers approach work at the bench and have already yielded new insights into brain tumours, multiple sclerosis, acute neurological insults such as stroke and seizures, and schizophrenia. The study of disease-related changes in gene expression is the first step in the long process in translation of genome research to the clinic. Eventually, the changes observed in microarray studies will need to be independently confirmed and we wil need to understand how gene expression changes translate into functional effects at the cellular level in the nervous system. Progress in these studies will translate into array-based disease classification schemes and help optimise therapy for individual patients based on gene expression patterns or their genetic background.     

Absence of association of a polymorphic GGC repeat at the 5' untranslated region of the reelin gene with schizophrenia

Reelin is an extracellular matrix glycoprotein that plays an important role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports suggest that reduced reelin expression is associated with human mental illnesses such as schizophrenia, mood disorders and autism. Human reelin cDNA has been cloned and contains a polymorphic GGC repeat at the 5' untranslated region. In view of the possible regulation of reelin gene expression by this GGC polymorphism, we investigated the association of the polymorphic GGC repeat with schizophrenia in a Chinese Han population from Taiwan. We found no differences of allelic and genotypic distributions of the polymorphic GGC triplets between 162 schizophrenic patients and 176 controls in this study. Our findings do not support the involvement of the polymorphic GGC triplets of the reelin gene in the pathogenesis of schizophrenia in the population studied.     

The other, forgotten genome: mitochondrial DNA and mental disorders.

This paper summarizes recent research on mitochondrial DNA (mtDNA)--which might be described as the "other, forgotten genome". Recent studies suggest the possible pathophysiological significance of mtDNA in schizophrenia and neurodegenerative and mood disorders. Decreased activity of the mitochondrial electron transport chain has been implicated in both Parkinson's and Alzheimer's disease and while age-related accumulation of mtDNA deletions has been suggested as a possible cause, there is no concrete evidence that particular mtDNA polymorphisms are responsible. In schizophrenia, the activity and/or mRNA expression of complex IV are involved, but the direction of the alteration is not the same and there is no evidence linking schizophrenia with mtDNA. In bipolar disorder, there is some evidence of parent-of-origin effects and association with mtDNA polymorphisms but further investigation is needed to elucidate the role of mtDNA in mental disorders.     

Patho- und Therapieepigenetik psychischer Erkrankungen

Epigenetic mechanisms, such as DNA methylation and histone modifications are biochemical alterations of the DNA or its spatial structure. They regulate gene function, can be modified by environmental influences and are temporally dynamic. In this review, the current state of knowledge regarding the role of epigenetics in the pathogenesis of mental disorders is summarized exemplarily for schizophrenia, depression, anxiety disorders and posttraumatic stress disorder. Additionally, findings on epigenetic alterations in the course of pharmacotherapeutic and psychotherapeutic interventions are presented. Epigenetic mechanisms have a central function at the crossroads between genes and environment and consequently in the vulnerability-stress model of mental disorders. Prospectively, in line with a precision medicine approach epigenetic profiles may represent useful markers of disease risk and therapy response or even constitute new druggable targets.     

Genetically modified animals as models for psychiatric diseases]

Animal models of mental disorders as well as physical disorders have been useful tools to elucidate pathophysiology of the complex disorders and develop new therapeutics. Transgenic mice including gene knockout animals have been produced by gene targeting technology. Monoamine system which is target of antipsychotics and antidepressants has very important roles in pathology of functional psychosis. In this review, we would like to introduce monoamine transporter knockout mice that we had generated as animal models of mental disorders including schizophrenia and drug abuse.     

The NMDA receptor co-agonists, D-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex

There is substantial evidence, both pharmacological and genetic, that hypofunction of the N-methyl-d-aspartate receptor (NMDAR) is a core pathophysiological feature of schizophrenia. There are morphological brain changes associated with schizophrenia, including perturbations in the dendritic morphology of cortical pyramidal neurons and reduction in cortical volume. Our experiments investigated whether these changes in dendritic morphology could be recapitulated in a genetic model of NMDAR hypofunction, the serine racemase knockout (SR-/-) mouse. Pyramidal neurons in primary somatosensory cortex (S1) of SR-/- mice had reductions in the complexity, total length, and spine density of apical and basal dendrites. In accordance with reduced cortical neuropil, SR-/- mice also had reduced cortical volume as compared to wild type mice. Analysis of S1 mRNA by DNA microarray and gene expression analysis revealed gene changes in SR-/- that are associated with psychiatric and neurologic disorders, as well as neurodevelopment. The microarray analysis also identified reduced expression of brain derived neurotrophic factor (BDNF) in SR-/- mice. Follow-up analysis by ELISA confirmed a reduction of BDNF protein levels in the S1 of SR-/- mice. Finally, S1 pyramidal neurons in glycine transporter heterozygote (GlyT1+/-) mutants, which display enhanced NMDAR function, had increased dendritic spine density. These results suggest that proper NMDAR function is important for the arborization and spine density of pyramidal neurons in cortex. Moreover, they suggest that NMDAR hypofunction might, in part, be contributing to the dendritic and synaptic changes observed in schizophrenia and highlight this signaling pathway as a potential target for therapeutic intervention.     

Neuronal Apoptosis Revealed by Genomic Analysis: Integrating Gene Expression Profiles with Functional Information

Apoptosis is a key physiological response that occurs during development of the nervous system, resulting in the death of nearly half of the embryonic neuronal population. Aberrant apoptotic mechanisms are thought to contribute significantly to many neurological disorders including Alzheimer’s disease. Although many experiments in the past have demonstrated the requirement of de novo gene expression during neuronal apoptosis, the complete spectrum of genes involved in distinct temporal domains is mostly unknown. To begin a comprehensive survey of the gene-based molecular mechanisms that underlie neuronal apoptosis, we have used the unprecedented experimental opportunities that genome sequences and the development of DNA microarray technology now provide to perform genome-wide expression analysis in different paradigms of neuronal apoptosis. In order to extract knowledge from gene expression information we have developed new informatics applications that enable clustering methods based on semantic characteristics, such as gene ontologies. This review will highlight the use of a genomic approach to identify the molecular program underlying neuronal apoptosis and illustrate how a semantic clustering method can be useful to extract more knowledge from microarray data.     

Lymphocytes as a neural probe: potential for studying psychiatric disorders

There is an increasing body evidence pointing to a close integration between the central nervous system (CNS) and immunological functions with lymphocytes playing therein a central role. The authors provide arguments to consider blood lymphocytes as a convenient probe of--an albeit--limited number of cellular functions, including gene expression. The use of brain biopsies of living patients is unrealistic for biochemical investigation, therefore lymphocytes may be a convenient and accessible alternative. Numerous studies showed similarities between receptor expression and mechanisms of transduction processes of cells in the nervous system (e.g. neurons and glia) and lymphocytes. In several neuropsychiatric disorders, alteration of metabolism and cellular functions in the CNS, as well as disturbances in the main neurotransmitter and hormonal systems are concomitant with altered function and metabolism of blood lymphocytes. We summarize relevant investigations on depression, stress, Alzheimer's disease (AD) and schizophrenia. New techniques such as cDNA microarray gene expression and proteomics may give clues to define molecular abnormalities in psychiatric disorders and could eventually reveal information for diagnostic and treatment purposes. Taken together, these considerations suggest that lymphocyte could reflect the metabolism of brain cells, and may be exploited as a neural and possible genetic probe in studies of psychiatric disorders.