Search

Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about the role of mosaic somatic mutations in the context of SCZ. Deep (239×) whole-genome sequencing (WGS) of brain neurons from 61 SCZ cases and 25 controls postmortem identified mutations occurring during prenatal neurogenesis. SCZ cases showed increased somatic variants in open chromatin, with increased mosaic CpG transversions (CpG>GpG) and T>G mutations at transcription factor binding sites (TFBSs) overlapping open chromatin, a result not seen in controls. Some of these variants alter gene expression, including SCZ risk genes and genes involved in neurodevelopment. Although these mutational processes can reflect a difference in factors indirectly involved in disease, increased somatic mutations at developmental TFBSs could also potentially contribute to SCZ.

With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct., Competing Interests: Declaration of competing interest There are no financial or other conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 10 4 -10 6 -bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer's disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.

As expanding genetic and genomic studies continue to implicate a growing list of variants contributing risk to neuropsychiatric disease, an important next step is to understand the functional impact and points of convergence of these risk factors. Here, with a focus on schizophrenia, we survey the most recent findings of the rare and common variants underlying genetic risk for schizophrenia. We discuss the ongoing efforts to validate these variants in post-mortem brain tissue, as well as new approaches to combine CRISPR-based genome engineering with patient-specific human induced pluripotent stem cell (hiPSC)-based models, in order to identify putative causal schizophrenia loci that regulate gene expression and cellular function. We consider the current limitations of hiPSC-based approaches as well as the future advances necessary to improve the fidelity of this human model. With the objective of utilizing patient genotype data to improve diagnosis and predict treatment response, the integration of CRISPR-genome engineering and hiPSC-based models represent an important strategy with which to systematically demonstrate the cell-type-specific effects of schizophrenia-associated variants., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Midbrain dopaminergic neurons (MDN) represent 0.0005% of the brain's neuronal population and mediate cognition, food intake, and metabolism. MDN are also posited to underlay the neurobiological dysfunction of schizophrenia (SCZ), a severe neuropsychiatric disorder that is characterized by psychosis as well as multifactorial medical co-morbidities, including metabolic disease, contributing to markedly increased morbidity and mortality. Paradoxically, however, the genetic risk sequences of psychosis and traits associated with metabolic disease, such as body mass, show very limited overlap., Methods: We investigated the genomic interaction of SCZ with medical conditions and traits, including body mass index (BMI), by exploring the MDN's "spatial genome," including chromosomal contact landscapes as a critical layer of cell type-specific epigenomic regulation. Low-input Hi-C protocols were applied to 5-10 × 10 3 dopaminergic and other cell-specific nuclei collected by fluorescence-activated nuclei sorting from the adult human midbrain., Results: The Hi-C-reconstructed MDN spatial genome revealed 11 "Euclidean hot spots" of clustered chromatin domains harboring risk sequences for SCZ and elevated BMI. Inter- and intra-chromosomal contacts interconnecting SCZ and BMI risk sequences showed massive enrichment for brain-specific expression quantitative trait loci (eQTL), with gene ontologies, regulatory motifs and proteomic interactions related to adipogenesis and lipid regulation, dopaminergic neurogenesis and neuronal connectivity, and reward- and addiction-related pathways., Conclusions: We uncovered shared nuclear topographies of cognitive and metabolic risk variants. More broadly, our PsychENCODE sponsored Hi-C study offers a novel genomic approach for the study of psychiatric and medical co-morbidities constrained by limited overlap of their respective genetic risk architectures on the linear genome.

Schizophrenia is a chronic and severe neuropsychiatric condition manifested by cognitive, emotional, affective, perceptual, and behavioral abnormalities. Despite decades of research, the biological substrates driving the signs and symptoms of the disorder remain elusive, thus hampering progress in the development of treatments aimed at disease etiologies. The recent emergence of human induced pluripotent stem cell (hiPSC)-based models has provided the field with a highly innovative approach to generate, study, and manipulate living neural tissue derived from patients, making possible the exploration of fundamental roles of genes and early-life stressors in disease-relevant cell types. Here, we begin with a brief overview of the clinical, epidemiological, and genetic aspects of the condition, with a focus on schizophrenia as a neurodevelopmental disorder. We then highlight relevant technical advancements in hiPSC models and assess novel findings attained using hiPSC-based approaches and their implications for disease biology and treatment innovation. We close with a critical appraisal of the developments necessary for both further expanding knowledge of schizophrenia and the translation of new insights into therapeutic innovations.

Schizophrenia is a debilitating psychiatric disorder with a complex genetic architecture and limited understanding of its neuropathology, reflected by the lack of diagnostic measures and effective pharmacological treatments. Geneticists have recently identified more than 145 risk loci comprising hundreds of common variants of small effect sizes, most of which lie in noncoding genomic regions. This review will discuss how the epigenetic toolbox can be applied to contextualize genetic findings in schizophrenia. Progress in next-generation sequencing, along with increasing methodological complexity, has led to the compilation of genome-wide maps of DNA methylation, histone modifications, RNA expression, and more. Integration of chromatin conformation datasets is one of the latest efforts in deciphering schizophrenia risk, allowing the identification of genes in contact with regulatory variants across 100s of kilobases. Large-scale multiomics studies will facilitate the prioritization of putative causal risk variants and gene networks that contribute to schizophrenia etiology, informing clinical diagnostics and treatment downstream.
., (© 2019, AICH Servier GroupCopyright © 2019 AICH Servier Group. All rights reserved.)

Both heritability and environment contribute to risk for schizophrenia. However, the molecular mechanisms of interactions between genetic and non-genetic factors remain unclear. Epigenetic regulation of neuronal genome may be a presumable mechanism in pathogenesis of schizophrenia. Here, we performed analysis of open chromatin landscape of gene promoters in prefrontal cortical (PFC) neurons from schizophrenic patients. We cataloged cell-type-based epigenetic signals of transcriptional start sites (TSS) marked by histone H3-K4 trimethylation (H3K4me3) across the genome in PFC from multiple schizophrenia subjects and age-matched control individuals. One of the top-ranked chromatin alterations was found in the major histocompatibility (MHC) locus on chromosome 6 highlighting the overlap between genetic and epigenetic risk factors in schizophrenia. The chromosome conformation capture (3C) analysis in human brain cells revealed the architecture of multipoint chromatin interactions between the schizophrenia-associated genetic and epigenetic polymorphic sites and distantly located HLA-DRB5 and BTNL2 genes. In addition, schizophrenia-specific chromatin modifications in neurons were particularly prominent for non-coding RNA genes, including an uncharacterized LINC01115 gene and recently identified BNRNA_052780. Notably, protein-coding genes with altered epigenetic state in schizophrenia are enriched for oxidative stress and cell motility pathways. Our results imply the rare individual epigenetic alterations in brain neurons are involved in the pathogenesis of schizophrenia.

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org .

To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type-specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type-specific disease risk vulnerabilities in spatial genome organization., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in the brain are highly enriched for schizophrenia SNP heritability. Accessible chromatin regions that overlap evolutionarily conserved regions exhibit an even higher heritability enrichment, indicating that sequence conservation can further refine functional risk variants. We identify few differences in chromatin accessibility between cases and controls, in contrast to thousands of age-related differential accessible chromatin regions. Altogether, we characterize chromatin accessibility in the human prefrontal cortex, the effect of schizophrenia and age on chromatin accessibility, and provide evidence that our dataset will allow for fine mapping of risk variants.

Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas. Thousands of significant histone quantitative trait loci were identified in neuronal and neuron-depleted samples. Risk variants for schizophrenia, depressive symptoms and neuroticism were significantly over-represented in neuronal H3K4me3 and H3K27ac landscapes. Our Resource, sponsored by PsychENCODE and CommonMind, highlights the critical role of cell-type-specific signatures at regulatory and disease-associated noncoding sequences in the human frontal lobe.

Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. Using genotypes and gene expression levels from post-mortem human brain samples (n = 467) reported by the CommonMind Consortium (CMC), we find that conditional eQTL are widespread; 63% of genes with primary eQTL also have conditional eQTL. In addition, genomic features associated with conditional eQTL are consistent with context-specific (e.g., tissue-, cell type-, or developmental time point-specific) regulation of gene expression. Integrating the 2014 Psychiatric Genomics Consortium schizophrenia (SCZ) GWAS and CMC primary and conditional eQTL data reveals 40 loci with strong evidence for co-localization (posterior probability > 0.8), including six loci with co-localization of conditional eQTL. Our co-localization analyses support previously reported genes, identify novel genes associated with schizophrenia risk, and provide specific hypotheses for their functional follow-up., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Chromosomal conformations, including promoter-enhancer loops, provide a critical regulatory layer for the transcriptional machinery. Therefore, schizophrenia, a common psychiatric disorder associated with broad changes in neuronal gene expression in prefrontal cortex and other brain regions implicated in psychosis, could be associated with alterations in higher-order chromatin. Here, we review early studies on spatial genome organization in the schizophrenia postmortem brain and discuss how integrative approaches using cell culture and animal model systems could gain deeper insight into the potential roles of higher-order chromatin for the neurobiology of and novel treatment avenues for common psychiatric disease., (Copyright © 2017. Published by Elsevier Inc.)

Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (MEF2C) motif enrichment in sequences surrounding the top scoring single-nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base-pair resolution in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within cis-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term Mef2c upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging in vivo by Mef2c-Dam adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders.

Large-scale consortia including the Psychiatric Genomics Consortium, the Common Minds Consortium, BrainSeq and PsychENCODE, and many other studies taken together provide increasingly detailed insights into the genetic and epigenetic risk architectures of schizophrenia (SCZ) and offer vast amounts of molecular information, but with largely unexplored therapeutic potential. Here we discuss how epigenomic studies in human brain could guide animal work to test the impact of disease-associated alterations in chromatin structure and function on cognition and behavior. For example, transcription factors such as MYOCYTE-SPECIFIC ENHANCER FACTOR 2C (MEF2C), or multiple regulators of the open chromatin mark, methyl-histone H3-lysine 4, are associated with the genetic risk architectures of common psychiatric disease and alterations in chromatin structure and function in diseased brain tissue. Importantly, these molecules also affect cognition and behavior in genetically engineered mice, including virus-mediated expression changes in prefrontal cortex (PFC) and other key nodes in the circuitry underlying psychosis. Therefore, preclinical and small laboratory animal work could target genomic sequences affected by chromatin alterations in SCZ. To this end, in vivo editing of enhancer and other regulatory non-coding DNA by RNA-guided nucleases including CRISPR-Cas, and designer transcription factors, could be expected to deliver pipelines for novel therapeutic approaches aimed at improving cognitive dysfunction and other core symptoms of SCZ., (© 2017 Wiley Periodicals, Inc.)

Objectives: Despite progress in identifying molecular pathophysiological processes in schizophrenia, valid biomarkers are lacking for both the disease and treatment response., Methods: This comprehensive review summarises recent efforts to identify molecular mechanisms on the level of protein and gene expression and epigenetics, including DNA methylation, histone modifications and micro RNA expression. Furthermore, it summarises recent findings of alterations in lipid mediators and highlights inflammatory processes. The potential that this research will identify biomarkers of schizophrenia is discussed., Results: Recent studies have not identified clear biomarkers for schizophrenia. Although several molecular pathways have emerged as potential candidates for future research, a complete understanding of these metabolic pathways is required to reveal better treatment modalities for this disabling condition., Conclusions: Large longitudinal cohort studies are essential that pair a thorough phenotypic and clinical evaluation for example with gene expression and proteome analysis in blood at multiple time points. This approach might identify biomarkers that allow patients to be stratified according to treatment response and ideally also allow treatment response to be predicted. Improved knowledge of molecular pathways and epigenetic mechanisms, including their potential association with environmental influences, will facilitate the discovery of biomarkers that could ultimately be effective tools in clinical practice.

The Psychiatric Genomics Consortium-Schizophrenia Workgroup (PGC-SCZ) recently identified 108 loci associated with increased risk for schizophrenia (SCZ). The vast majority of these variants reside within non-coding sequences of the genome and are predicted to exert their effects by affecting the mechanism of action of cis regulatory elements (CREs), such as promoters and enhancers. Although a number of large-scale collaborative efforts (e.g. ENCODE) have achieved a comprehensive mapping of CREs in human cell lines or tissue homogenates, it is becoming increasingly evident that many risk-associated variants are enriched for expression Quantitative Trait Loci (eQTLs) and CREs in specific tissues or cells. As such, data derived from previous research endeavors may not capture fully cell-type and/or region specific changes associated with brain diseases. Coupling recent technological advances in genomics with cell-type specific methodologies, we are presented with an unprecedented opportunity to better understand the genetics of normal brain development and function and, in turn, the molecular basis of neuropsychiatric disorders. In this review, we will outline ongoing efforts towards this goal and will discuss approaches with the potential to shed light on the mechanism(s) of action of cell-type specific cis regulatory elements and their putative roles in disease, with particular emphasis on understanding the manner in which the epigenome and CREs influence the etiology of SCZ., Competing Interests: The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Published by Elsevier B.V.)

Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function as well as likely abnormalities in glial cells. While genetic factors are important in the etiology of most mental disorders, the relatively high rates of discordance among identical twins, particularly for depression and other stress-related syndromes, clearly indicate the importance of additional mechanisms. Environmental factors such as stress are known to play a role in the onset of these illnesses. Exposure to such environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental versus adult exposures. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and the aberrant epigenetic regulation that underlies this dysregulation is a unifying theme in psychiatric disorders. Here, we provide a progress report of epigenetic studies of the three major psychiatric syndromes, depression, schizophrenia, and bipolar disorder. We review the literature derived from animal models of these disorders as well as from studies of postmortem brain tissue from human patients. While epigenetic studies of mental illness remain at early stages, understanding how environmental factors recruit the epigenetic machinery within specific brain regions to cause lasting changes in disease susceptibility and pathophysiology is revealing new insight into the etiology and treatment of these conditions., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2015.)

Schizophrenia, a major psychiatric disorder defined by delusions and hallucinations, among other symptoms, often with onset in early adulthood, is potentially associated with molecular and cellular alterations in parvalbumin-expressing fast spiking interneurons and other constituents of the cortical inhibitory GABAergic circuitry. The underlying mechanisms, including the role of disease-associated risk factors operating in adolescence such as drug abuse and social stressors, remain incompletely understood. Here, we summarize emerging findings from animal models, highlighting the ability of parvalbuminergic interneurons (PVI) to induce, during the juvenile period, long-term plastic changes in prefrontal and visual cortex, thereby altering perception, cognition and behavior in the adult. Of note, molecular alterations in PVI from subjects with schizophrenia, including downregulated expression of a subset of GABAergic genes, have also been found in juvenile stress models of the disorder. Some of the transcriptional alterations observed in schizophrenia postmortem brain could be linked to changes in the epigenetic architecture of GABAergic gene promoters, including dysregulated DNA methylation, histone modification patterns and disruption of promoter-enhancer interactions at site of chromosomal loop formations. Therefore, we predict that, in the not-to-distant future, PVI- and other cell-type specific epigenomic mappings in the animal model and human brain will provide novel insights into the pathophysiology of schizophrenia and related psychotic diseases, including the role of cortical GABAergic circuitry in shaping long-term plasticity and cognitive function of the cerebral cortex., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Expression of GAD1 GABA synthesis enzyme is highly regulated by neuronal activity and reaches mature levels in the prefrontal cortex not before adolescence. A significant portion of cases diagnosed with schizophrenia show deficits in GAD1 RNA and protein levels in multiple areas of adult cerebral cortex, possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons essential for network synchronization and cognition. Here, we review 20years of progress towards a better understanding of disease-related regulation of GAD1 gene expression. For example, deficits in cortical GAD1 RNA in some cases of schizophrenia are associated with changes in the epigenetic architecture of the promoter, affecting DNA methylation patterns and nucleosomal histone modifications. These localized chromatin defects at the 5' end of GAD1 are superimposed by disordered locus-specific chromosomal conformations, including weakening of long-range promoter-enhancer loopings and physical disconnection of GAD1 core promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including developmentally regulated higher order chromatin compromised by the disease process, together with exploration of locus-specific epigenetic interventions in animal models, could pave the way for future treatments of psychosis and schizophrenia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Advances in molecular genetics, fueled by the results of large-scale genome-wide association studies, meta-analyses, and mega-analyses, have provided the means of identifying genetic risk factors for human disease, thereby enriching our understanding of the functionality of the genome in the post-genomic era. In the past half-decade, research on neuropsychiatric disorders has reached an important milestone: the identification of susceptibility genes reliably associated with complex psychiatric disorders at genome-wide levels of significance. This age of discovery provides the groundwork for follow-up studies designed to elucidate the mechanism(s) by which genetic variants confer susceptibility to these disorders. The gene encoding zinc-finger protein 804 A (ZNF804A) is among these candidate genes, recently being found to be strongly associated with schizophrenia and bipolar disorder via one of its non-coding mutations, rs1344706. Neurobiological, molecular, and bioinformatic analyses have improved our understanding of ZNF804A in general and this variant in particular; however, more work is needed to establish the mechanism(s) by which ZNF804A variants impinge on the biological substrates of the two disorders. Here, we review literature recently published on ZNF804A, and analyze critical concepts related to the biology of ZNF804A and the role of rs1344706 in schizophrenia and bipolar disorder. We synthesize the results of new bioinformatic analyses of ZNF804A with key elements of the existing literature and knowledge base. Furthermore, we suggest some potentially fruitful short- and long-term research goals in the assessment of ZNF804A., (© 2014 Wiley Periodicals, Inc.)

A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Schizophrenia is a major psychiatric disorder that lacks a unifying neuropathology, while currently available pharmacological treatments provide only limited benefits to many patients. This review will discuss how the field of neuroepigenetics could contribute to advancements of the existing knowledge on the neurobiology and treatment of psychosis. Genome-scale mapping of DMA methylation, histone modifications and variants, and chromosomal loopings for promoter-enhancer interactions and other epigenetic determinants of genome organization and function are likely to provide important clues about mechanisms contributing to dysregulated expression of synaptic and metabolic genes in schizophrenia brain, including the potential links to the underlying genetic risk architecture and environmental exposures. In addition, studies in animal models are providing a rapidly increasing list of chromatin-regulatory mechanisms with significant effects on cognition and complex behaviors, thereby pointing to the therapeutic potential of epigenetic drug targets in the nervous system.

Less than 1.5% of the human genome encodes protein. However, vast portions of the human genome are subject to transcriptional and epigenetic regulation, and many noncoding regulatory DNA elements are thought to regulate the spatial organization of interphase chromosomes. For example, chromosomal "loopings" are pivotal for the orderly process of gene expression, by enabling distal regulatory enhancer or silencer elements to directly interact with proximal promoter and transcription start sites, potentially bypassing hundreds of kilobases of interspersed sequence on the linear genome. To date, however, epigenetic studies in the human brain are mostly limited to the exploration of DNA methylation and posttranslational modifications of the nucleosome core histones. In contrast, very little is known about the regulation of supranucleosomal structures. Here, we show that chromosome conformation capture, a widely used approach to study higher-order chromatin, is applicable to tissue collected postmortem, thereby informing about genome organization in the human brain. We introduce chromosome conformation capture protocols for brain and compare higher-order chromatin structures at the chromosome 6p22.2-22.1 schizophrenia and bipolar disorder susceptibility locus, and additional neurodevelopmental risk genes, (DPP10, MCPH1) in adult prefrontal cortex and various cell culture systems, including neurons derived from reprogrammed skin cells. We predict that the exploration of three-dimensional genome architectures and function will open up new frontiers in human brain research and psychiatric genetics and provide novel insights into the epigenetic risk architectures of regulatory noncoding DNA., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Little is known about chromosomal loopings involving proximal promoter and distal enhancer elements regulating GABAergic gene expression, including changes in schizophrenia and other psychiatric conditions linked to altered inhibition. Here, we map in human chromosome 2q31 the 3D configuration of 200 kb of linear sequence encompassing the GAD1 GABA synthesis enzyme gene locus, and we describe a loop formation involving the GAD1 transcription start site and intergenic noncoding DNA elements facilitating reporter gene expression. The GAD1-TSS(-50kbLoop) was enriched with nucleosomes epigenetically decorated with the transcriptional mark, histone H3 trimethylated at lysine 4, and was weak or absent in skin fibroblasts and pluripotent stem cells compared with neuronal cultures differentiated from them. In the prefrontal cortex of subjects with schizophrenia, GAD1-TSS(-50kbLoop) was decreased compared with controls, in conjunction with downregulated GAD1 expression. We generated transgenic mice expressing Gad2 promoter-driven green fluorescent protein-conjugated histone H2B and confirmed that Gad1-TSS(-55kbLoop), the murine homolog to GAD1-TSS(-50kbLoop), is a chromosomal conformation specific for GABAergic neurons. In primary neuronal culture, Gad1-TSS(-55kbLoop) and Gad1 expression became upregulated when neuronal activity was increased. We conclude that 3D genome architectures, including chromosomal loopings for promoter-enhancer interactions involved in the regulation of GABAergic gene expression, are conserved between the rodent and primate brain, and subject to developmental and activity-dependent regulation, and disordered in some cases with schizophrenia. More broadly, the findings presented here draw a connection between noncoding DNA, spatial genome architecture, and neuronal plasticity in development and disease.

Notwithstanding the considerable advances in the treatment options for schizophrenia, the cognitive symptoms in particular are not receptive to antipsychotic treatment and considered one of the main predictors for poor social and functional outcome of the disease. Recent findings in preclinical model systems indicate that epigenetic modulation might emerge as a promising target for the treatment of cognitive disorders. The aim of this review is to introduce some of the principles of chromatin biology to the reader and to discuss a possible role in the neurobiology and pathophysiology of schizophrenia. We will discuss potential epigenetic targets for drug therapy, including histone deacetylase inhibitors (HDACi). In a second part, conceptual and practical challenges associated with clinical trials of chromatin-modifying drugs in psychiatric patient populations are discussed, including safety profiles, the potential for adverse effects and general issues revolving around pharmacokinetics and pharmacodynamics. Additional investigations are required in order to fully evaluate the potential of HDACi and similar "epigenetic therapies" as novel treatment options for schizophrenia and other psychotic disease.

Estrogen signaling pathways affect cortical function and metabolism, are thought to play a role in the pathophysiology of schizophrenia, and exert neuroprotective effects in female subjects at risk. However, the molecular signatures of estrogen signaling in normal and diseased cerebral cortex remain largely unexplored. Expression of the estrogen-sensitive small RNA, microRNA-30b (miR-30b), was studied in 30 controls and 30 matched samples from subjects diagnosed with schizophrenia from prefrontal cortex (PFC), as well as in 23 samples from parietal cortex (12 controls and 11 schizophrenia cases). The majority of case and control samples were genotyped for an estrogen receptor α (Esr1) sequence variant (rs2234693) previously associated with genetic risk, and a subset of them were subjected to further analysis to determine expression of mature and precursor forms of miR-30b (pre/pri-miR-30b). Gender-dimorphic expression was also explored in mouse frontal cortex and hippocampus. A significant interaction between gender and diagnosis was discovered for changes in mature miR-30b levels, so that miR-30b expression was significantly reduced in the cerebral cortex of female but not male subjects with schizophrenia. In addition, disease-related changes in miR-30b expression in a subset of female subjects were further modulated by Esr1 genotype. Changes after antipsychotic drug exposure remained insignificant. These preliminary findings point to the possibility that disease-related changes in the expression of small noncoding RNAs such as miR-30b in schizophrenia could be influenced by gender and potentially regulated by estrogen signaling.

Cortical and subcortical dysfunction in schizophrenia includes altered expression of RNA and proteins involved in neurotransmission, metabolism, myelination and other functions. The molecular mechanisms underlying this type of alteration remain largely unknown. Here, we summarize findings from postmortem brain studies and argue that transcriptional dysregulation, including changes in DNA and histone modifications involved in epigenetic control of gene expression, as well as microRNA-mediated post-transcriptional mechanisms contribute to the neurobiology of schizophrenia., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Increased density and altered spatial distribution of subcortical white matter neurons (WMNs) represents one of the more well replicated cellular alterations found in schizophrenia and related disease. In many of the affected cases, the underlying genetic risk architecture for these WMN abnormalities remains unknown. Increased density of neurons immunoreactive for Microtubule-Associated Protein 2 (MAP2) and Neuronal Nuclear Antigen (NeuN) have been reported by independent studies, though there are negative reports as well; additionally, group differences in some of the studies appear to be driven by a small subset of cases. Alterations in markers for inhibitory (GABAergic) neurons have also been described. For example, downregulation of neuropeptide Y (NPY) and nitric oxide synthase (NOS1) in inhibitory WMN positioned at the gray/white matter border, as well as altered spatial distribution, have been reported. While increased density of WMN has been suggested to reflect disturbance of neurodevelopmental processes, including neuronal migration, neurogenesis, and cell death, alternative hypotheses--such as an adaptive response to microglial activation in mature CNS, as has been described in multiple sclerosis--should also be considered. We argue that larger scale studies involving hundreds of postmortem specimens will be necessary in order to clearly establish the subset of subjects affected. Additionally, these larger cohorts could make it feasible to connect the cellular pathology to environmental and genetic factors implicated in schizophrenia, bipolar disorder, and autism. These could include the 22q11 deletion (Velocardiofacial/DiGeorge) syndrome, which in some cases is associated with neuronal ectopias in white matter., (Copyright © 2010 ISDN. Published by Elsevier Ltd. All rights reserved.)

Dysfunction of cerebral cortex and other brain regions in schizophrenia is often accompanied by dysregulated expression of numerous genes. However, the underlying genetic risk architecture remains unclear for a large majority of cases. Therefore, the study of epigenetic regulators of gene expression, including covalent modifications of DNA and nucleosome core histones, offers an attractive alternative to further explore the molecular pathology of schizophrenia beyond the level of RNA quantification. Several studies reported alterations in DNA cytosine methylation and histone methylation at specific genes and promoters in postmortem brain of subjects with schizophrenia, often in conjunction with changes in levels of the corresponding RNAs. While evidence for such "epigenetic dysregulation" is increasing, many of the reported alterations await independent replication. Interestingly, studies across the lifespan indicate that DNA and histone methylation markings are developmentally regulated in human cerebral cortex, suggesting that at least some of the epigenetic changes in the brain of adult subjects with schizophrenia reflect disordered neurodevelopment., (Copyright 2009 Elsevier Inc. All rights reserved.)

Epigenetic regulators of gene expression including DNA cytosine methylation and posttranslational histone modifications could play a role for some of the molecular alterations associated with schizophrenia. For example, in prefrontal cortex of subjects with schizophrenia, abnormal DNA or histone methylation at sites of specific genes and promoters is associated with changes in RNA expression. These findings are of interest from a neurodevelopmental perspective because there is increasing evidence that epigenetic markings for a substantial portion of genes and loci are highly regulated during the first years of life. Furthermore, there is circumstantial evidence that a subset of antipsychotic drugs, including the atypical, Clozapine, interfere with chromatin remodeling mechanisms. Challenges for the field include (1) no clear consensus yet regarding disease-associated changes, (2) the lack of cell-specific chromatin assays which makes it difficult to ascribe epigenetic alterations to specific cell populations, and (3) lack of knowledge about the stability or turnover of epigenetic markings at specific loci in (brain) chromatin. Despite these shortcomings, the study of DNA and histone modifications in chromatin extracted from diseased and control brain tissue is likely to provide valuable insight into the genomic risk architecture of schizophrenia, particularly in the large majority of cases for which a straightforward genetic cause still remains elusive,

Background: Increased neuronal density in prefrontal, parietal, and temporal white matter of schizophrenia subjects is thought to reflect disordered neurodevelopment; however, it is not known if this cellular alteration affects the cingulate cortex and whether similar changes exist in bipolar disorder., Method: Eighty-two postmortem specimens (bipolar 15, schizophrenia 22, control 45) were included in this clinical study. Densities for two neuronal markers, neuron-specific nuclear protein (NeuN) and neuregulin 1 alpha (NRG), were determined in white matter up to 2.5 mm beneath the anterior cingulate cortex; density of NeuN immunopositive neurons (NeuN+) was also determined for a subset of cases in prefrontal cortex. Changes during normal development were monitored in a separate cohort of 14 brains., Results: Both the schizophrenia and bipolar cohorts demonstrated a twofold increase in NeuN+ density in cingulate white matter; this effect could be attributed to approximately 25% of cases that exceeded the second standard deviation from control subjects. Similar changes were observed in prefrontal cortex. In contrast density of NRG expressing neurons was unaltered. Cases with increased NeuN+ densities in two-dimensional (2-D) counts also showed a pronounced, > fivefold elevation in NeuN+ nuclei per cubic millimeter. Additionally, the developmental cohort demonstrated a 75% decline in NeuN+ neuronal density during the first postnatal year but was stable thereafter., Conclusions: Increased neuronal density in white matter of cingulate cortex in schizophrenia provides further evidence that this alteration occurs in multiple cortical areas. Similar changes in some cases with bipolar illness suggest that the two disorders may share a common underlying defect in late prenatal or early postnatal neurodevelopment.

Background: Prefrontal deficits in gamma-aminobutyric acid (GABA)ergic gene expression, including neuropeptide Y (NPY), somatostatin (SST), and parvalbumin (PV) messenger RNAs (mRNAs), have been reported for multiple schizophrenia cohorts. Preclinical models suggest that a subset of these GABAergic markers (NPY/SST) is regulated by brain-derived neurotrophic factor (BDNF), which in turn is under the inhibitory influence of small noncoding RNAs. However, it remains unclear if these mechanisms are important determinants for dysregulated NPY and SST expression in prefrontal cortex (PFC) of subjects with schizophrenia., Methods: Using a postmortem case-control design, the association between BDNF protein, NPY/SST/PV mRNAs, and two BDNF-regulating microRNAs (miR-195 and miR-30a-5p) was determined in samples from the PFC of 20 schizophrenia and 20 control subjects. Complementary studies were conducted in cerebral cortex of mice subjected to antipsychotic treatment or a brain-specific ablation of the Bdnf gene., Results: Subjects with schizophrenia showed deficits in NPY and PV mRNAs. Within-pair differences in BDNF protein levels showed strong positive correlations with NPY and SST and a robust inverse association with miR-195 levels, which in turn were not affected by antipsychotic treatment or genetic ablation of Bdnf., Conclusions: Taken together, these results suggest that prefrontal deficits in a subset of GABAergic mRNAs, including NPY, are dependent on the regional supply of BDNF, which in turn is fine-tuned through a microRNA (miRNA)-mediated mechanism.

The etiology of the major psychotic disorders, including schizophrenia and bipolar disorder, remains poorly understood. Postmortem brain studies have revealed altered expression of multiple mRNAs, affecting neurotransmission, metabolism, myelination and other functions. Epigenetic mechanisms could be involved, because for a limited number of genes, the alterations of mRNA levels have been linked to inverse DNA methylation changes at sites of the corresponding promoters. However, results from independent studies have been inconsistent, and when expressed in quantitative terms, disease-related methylation changes appear to be comparatively subtle. A recent study identified approximately 100 loci with altered CpG methylation in schizophrenia or bipolar disorder, the majority of which were gender-specific. Additional work will be necessary to clarify the origin and timing of these methylation changes in psychosis and to determine the specific cell types affected in the diseased brain.

Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters (GAD2, NPY, SST) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5' end of GAD1. Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, Gad1 H3K4 (tri)methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D2 and D3 receptors, suggesting that blockade of D2-like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia.

The role of DNA cytosine methylation, an epigenetic regulator of chromatin structure and function, during normal and pathological brain development and aging remains unclear. Here, we examined by MethyLight PCR the DNA methylation status at 50 loci, encompassing primarily 5' CpG islands of genes related to CNS growth and development, in temporal neocortex of 125 subjects ranging in age from 17 weeks of gestation to 104 years old. Two psychiatric disease cohorts--defined by chronic neurodegeneration (Alzheimer's) or lack thereof (schizophrenia)--were included. A robust and progressive rise in DNA methylation levels across the lifespan was observed for 8/50 loci (GABRA2, GAD1, HOXA1, NEUROD1, NEUROD2, PGR, STK11, SYK) typically in conjunction with declining levels of the corresponding mRNAs. Another 16 loci were defined by a sharp rise in DNA methylation levels within the first few months or years after birth. Disease-associated changes were limited to 2/50 loci in the Alzheimer's cohort, which appeared to reflect an acceleration of the age-related change in normal brain. Additionally, methylation studies on sorted nuclei provided evidence for bidirectional methylation events in cortical neurons during the transition from childhood to advanced age, as reflected by significant increases at 3, and a decrease at 1 of 10 loci. Furthermore, the DNMT3a de novo DNA methyl-transferase was expressed across all ages, including a subset of neurons residing in layers III and V of the mature cortex. Therefore, DNA methylation is dynamically regulated in the human cerebral cortex throughout the lifespan, involves differentiated neurons, and affects a substantial portion of genes predominantly by an age-related increase.

Dysfunction of prefrontal cortex in schizophrenia includes changes in GABAergic mRNAs, including decreased expression of GAD1, encoding the 67 kDa glutamate decarboxylase (GAD67) GABA synthesis enzyme. The underlying molecular mechanisms remain unclear. Alterations in DNA methylation as an epigenetic regulator of gene expression are thought to play a role but this hypothesis is difficult to test because no techniques are available to extract DNA from GAD1 expressing neurons efficiently from human postmortem brain. Here, we present an alternative approach that is based on immunoprecipitation of mononucleosomes with anti-methyl-histone antibodies differentiating between sites of potential gene expression as opposed to repressive or silenced chromatin. Methylation patterns of CpG dinucleotides at the GAD1 proximal promoter and intron 2 were determined for each of the two chromatin fractions separately, using a case-control design for 14 schizophrenia subjects affected by a decrease in prefrontal GAD1 mRNA levels. In controls, the methylation frequencies at CpG dinucleotides, while overall higher in repressive as compared to open chromatin, did not exceed 5% at the proximal GAD1 promoter and 30% within intron 2. Subjects with schizophrenia showed a significant, on average 8-fold deficit in repressive chromatin-associated DNA methylation at the promoter. These results suggest that chromatin remodeling mechanisms are involved in dysregulated GABAergic gene expression in schizophrenia.

The 67 and 65 kDa isoforms of glutamic acid decarboxylase, the key enzymes for GABA biosynthesis, are expressed at altered levels in postmortem brain of subjects diagnosed with schizophrenia and related disorders, including autism and bipolar illness. The predominant finding is a decrease in GAD67 mRNA levels, affecting multiple brain regions, including prefrontal and temporal cortex. Postmortem studies, in conjunction with animal models, identified several mechanisms that contribute to the dysregulation of GAD67 in cerebral cortex. These include disordered connectivity formation during development, abnormal expression of Reelin and neural cell adhesion molecule (NCAM) glycoproteins, defects in neurotrophin signaling and alterations in dopaminergic and glutamatergic neurotransmission. These mechanisms are likely to operate in conjunction with genetic risk factors for psychosis, including sequence polymorphisms residing in the promoter of GAD1 (2q31), the gene encoding GAD67. We propose an integrative model, with multiple molecular and cellular mechanisms contributing to transcriptional dysregulation of GAD67 and cortical dysfunction in psychosis.

Background: Schizophrenia is frequently accompanied by hypometabolism and altered gene expression in the prefrontal cortex. Cellular metabolism regulates chromatin structure, including covalent histone modifications, which are epigenetic regulators of gene expression., Objective: To test the hypothesis that down-regulated metabolic gene expression is associated with histone modification changes in the prefrontal cortex of subjects with schizophrenia., Design and Subjects: Histones and gene transcripts were profiled in the postmortem prefrontal cortex of 41 subjects with schizophrenia and 41 matched controls. The phosphorylation, acetylation, and methylation of 6 lysine, serine, and arginine residues of histones H3 and H4 were examined together with 16 metabolic gene transcripts using serial immunoblotting, immunohistochemical analysis, custom-made complementary DNA arrays, and quantitative real-time reverse transcriptase-polymerase chain reaction., Results: Subjects with schizophrenia, as a group, showed no significant alterations in histone profiles or gene expression. In a subgroup of 8 patients with schizophrenia, levels of H3-(methyl)arginine 17, H3meR17, exceeded control values by 30%, and this was associated with the decreased expression of 4 metabolic transcripts., Conclusions: High levels of H3-(methyl)arginine 17 are associated with down-regulated metabolic gene expression in the prefrontal cortex of a subset of subjects with schizophrenia. Histone modifications may contribute to the pathogenesis of prefrontal dysfunction in schizophrenia.

Background: The neurotransmitters dopamine and glutamate have been implicated in the prefrontal dysfunction associated with schizophrenic illness. Studies suggest that the D1 subclass of dopamine receptor and the N-methyl-D-aspartate subclass of glutamate receptor are involved in this prefrontal dysfunction. These 2 receptors regulate, in opposing directions, the amount of phosphorylated activated DARPP-32, a potent inhibitor of protein phosphatase 1 that modulates the activity of several classes of receptors and ion channels. Thus, DARPP-32 occupies a key regulatory position, and may play an important role in the pathophysiological changes in dopamine and glutamate function reported in patients with schizophrenia., Methods: The amounts of DARPP-32, synapsin I, and the alpha subunit of calcium/calmodulin-dependent protein kinase II were measured by immunoblotting in postmortem samples from 14 schizophrenic subjects and their age-, gender-, and autolysis time-matched control subjects. Possible confounding influences of neuroleptic treatment were analyzed by comparing subjects with Alzheimer disease who were and were not treated with neuroleptic agents., Results: DARPP-32 was significantly reduced in the dorsolateral prefrontal cortex in more schizophrenic subjects relative to matched controls. The ratios of 2 other synaptic phosphoproteins, synapsin I and the alpha subunit of calcium/calmodulin-dependent protein kinase II, did not differ between schizophrenic and control subjects, nor between subjects with Alzheimer disease who were and were not treated with neuroleptic agents., Conclusions: Our findings are consistent with a selective reduction in DARPP-32 levels in schizophrenic subjects. This may be involved in the prefrontal dysfunction associated with schizophrenia.

Background: The cortical subplate is a transitory structure involved in the formation of connections in developing cerebral cortex. Interstitial neurons, normally present in subcortical white matter (WM) of the adult brain, have escaped the programmed cell death that eliminates most subplate neurons. Previous investigations indicated a maldistribution of one population of interstitial neurons in the WM of brains of schizophrenic patients, suggesting a defect of the subplate during brain development., Methods: Three histochemically or immunocytochemically defined neuronal populations were studied in WM beneath the middle frontal gyrus of 20 schizophrenic patients and 20 matched control subjects., Results: Brains of schizophrenic patients showed significant changes in the distribution of the three neuronal populations: microtubule-associated protein 2 and nonphosphorylated neurofilament-immunoreactive neurons showed a decreased density in superficial WM and an increased density in deeper WM. Nicotinamide adenine dinucleotide phosphate-diaphorase neurons were reduced in superficial WM and showed variable densities in deeper WM. Thirty-five percent of the brains of schizophrenic patients but no brains of the control subjects showed a maldistribution of neurons toward deeper WM with at least two of the three markers. Changes in neuronal distribution were not linked to age, gender, autolysis time, or subtype of schizophrenia., Conclusions: Selective displacement of interstitial WM neurons in the frontal lobe of brains of schizophrenic patients may indicate alteration in the migration of subplate neurons or in the pattern of programmed cell death. Both could lead to defective cortical circuitry in the brains of schizophrenic patients.