BACKGROUND:Schizophrenia (SZ) is a long-term psychiatric condition that affects cognition, thought processing, emotional regulation, and behavior. Epigenetic modifications during pregnancy or early postnatal development increase vulnerability to SZ by disrupting the balance of GABAergic-glutamatergic neurotransmission. OBJECTIVE:The association between GABAergic interneurons and inflammation has been increasingly investigated. Systemic inflammation alters the expression of GABAergic interneuron markers, including somatostatin and parvalbumin, in various brain regions. These modifications contribute to microglial reactivity and neuronal damage. Neuroinflammation, driven by reactive microglia, is recognized as a pathophysiological mechanism associated with SZ and its cognitive domain. METHODS:In this review, we addressed the role of GABAergic interneurons and examined how neuroinflammation interacts with epigenetic changes, contributing to SZ development. Network analysis was used to reveal potential molecular targets for pharmacological studies. RESULTS:Functional analysis of TLR4 and NF-κB1 revealed molecular factors relevant to inflammatory processes and gene regulation. Network analysis of GABA receptor A type 1 and TNF identified molecular targets suitable for pharmacological intervention. Protein-chemical interaction analysis showed that TLR4 and NF-κB1 interact with the polyphenols quercetin, epigallocatechin gallate, and resveratrol, all of which exert anti-inflammatory effects via epigenetic mechanisms, as well as the HDAC inhibitor valproic acid. CONCLUSION:Epigenetic changes in GABAergic interneurons may facilitate circuit imbalance and exacerbate psychotic symptoms. Epigenetic alterations in cortical parvalbumin-positive GABAergic interneurons and modifications in glutamate-mediated excitatory neurotransmission during early neurodevelopment contribute to the pathogenesis of SZ, alongside concomitant neuroinflammation. Targeting these epigenetic modifications and neuroinflammation may reveal new treatment strategies for the pharmacological management of SZ.

According to the omnigenic model for the inheritance of common traits proposed by Jonathan Pritchard’s group in 2017, there are a very large number of genetic variants underlying common traits spread across the genome. Causal variants are of two types: core genes that have direct roles in disease pathogenesis that contribute only a small amount to total heritability and peripheral genes that are much more in number than core genes and that cumulatively contribute maximally to trait heritability. The same group proposed in 2019 that peripheral genes have indirect effects by acting in trans. The authors propose that most heritability is due to weak trans-expression quantitative trait loci (trans-eQTL) single nucleotide polymorphisms (SNPs) whose effects are mediated by peripheral genes that influence the expression of core genes. In 2018, we provided evidence for an epigenetic-based omnigenic model for the inheritance of common psychiatric disorders. In the current article, we discuss the possible role of genes underlying trans-acting factors, namely, non-coding RNAs and transcription factors, in the pathogenesis of common psychiatric disorders.

The enzyme KDM1A encoded by KDM1A and also known as lysine-specific demethylase 1 (LSD1) plays important roles in the development and function of the brain. Vafidemstat is a KDM1A inhibitor that has shown beneficial effects in preclinical and clinical trials for the treatment of neuropsychiatric disorders, including borderline personality disorder (BPD), autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD). This article reviews available preclinical and clinical data on the use of vafidemstat in the treatment of these disorders. Vafidemstat appears to be a potential new and safe drug for the treatment of these disorders.

Biomarkers represent biological measures that reflect a given phenotypic trait, behavior, or physiological condition. They are used in a large number of biomedical fields to compare normal biological with pathogenic processes. In this context, they are useful in clinical diagnoses, progression of disease, and responsiveness to pharmacotherapies, among others. In the context of psychiatric or neuropsychiatric disorders, they are most often studied in blood, saliva, mucous, urine, or other readily accessible biological materials from patients. In the context of developing biomarkers it is important to compare data from patient and control groups to better understand how to interpret differences. Epigenetic biomarkers refer to biomarkers that are derived from the epigenome that can consist of modifications of DNA, various histone marks, and expression of long noncoding RNAs and miRNAs. In this chapter, we describe numerous types of biomarkers that are being investigated in patients with known psychiatric disorders. One of the bigger problems researchers encounter in the hunt for diagnostic biomarkers is the vast heterogeneity of the human genome and the large numbers of samples that are needed to obtain statistically reliable and reproducible genome-wide data.

Stress-inducing events during pregnancy are associated with aberrant neurodevelopment resulting in adverse psychiatric outcomes, including autism spectrum disorder (ASD). While numerous preclinical models for the study of ASD are frequently generated using C57BL/6J mice, few studies have investigated the effects of prenatal stress on this genetic background. In the current manuscript, we stressed C57BL/6 dams during gestation and examined numerous behavioral and molecular endophenotypes in the adult male and female offspring to characterize the resultant phenotype as compared with offspring born from nonstressed (NS) dams. Adult mice born from prenatal restraint stressed (PRS) dams demonstrated reduced sociability and reciprocal social interaction along with increased marble burying behaviors relative to mice born from nonstressed control dams. Differential expression of genes related to excitatory and inhibitory neurotransmission was evaluated in the medial prefrontal cortex, amygdala, hippocampus, nucleus accumbens and caudate putamen via qRT-PCR. The male PRS mouse behavioral phenotype coincided with aberrant expression of glutamate and GABA marker genes (e.g., Grin1, Grin2b, Gls, Gat1, Reln) in neural substrates of social behavior. Rescue of the male PRS sociability deficit by a known antipsychotic with epigenetic properties (i.e., clozapine (5 mg/kg) + 18 hr washout) indicated possible epigenetic regulation of genes that govern sociability. Clozapine treatment increased the expression levels of genes involved in DNA methylation, histone methylation, and histone acetylation in the nucleus accumbens. Identification of etiology-specific mechanisms underlying clinically relevant behavioral phenotypes may ultimately provide novel therapeutic interventions for the treatment of psychiatric disorders including ASD.

BACKGROUND: The ventral tegmental area (VTA) is a dopaminergic brain area that is critical in the development and maintenance of addiction. During withdrawal from chronic ethanol exposure, the response of VTA neurons to GABA (gamma-aminobutyric acid) is reduced through an epigenetically regulated mechanism. In the current study, a wholegenome transcriptomic approach was used to investigate the underlying molecular mechanism of GABA hyposensitivity in the VTA during withdrawal after chronic ethanol exposure.METHODS: We performed RNA sequencing of the VTA of Sprague Dawley male rats withdrawn for 24 hours from a chronic ethanol diet as well as sequencing of the VTA of control rats fed the Lieber-DeCarli diet. RNA sequencing data were analyzed using weighted gene coexpression network analysis to identify modules that contained coexpressed genes. Validation was performed with quantitative polymerase chain reaction, gas chromatography-mass spectrometry, and electrophysiological assays.RESULTS: Pathway and network analysis of weighted gene coexpression network analysis module 1 revealed a significant downregulation of genes associated with the cholesterol synthesis pathway. Consistent with this association, VTA cholesterol levels were significantly decreased during withdrawal. Chromatin immunoprecipitation indicated a decrease in levels of acetylated H3K27 at the transcriptional control regions of these genes. Electrophysiological studies in VTA slices demonstrated that GABA hyposensitivity during withdrawal was normalized by addition of exogenous cholesterol. In addition, inhibition of cholesterol synthesis produced GABA hyposensitivity, which was reversed by adding exogenous cholesterol to VTA slices.CONCLUSIONS: These results suggest that decreased expression of cholesterol synthesis genes may regulate GABA hyposensitivity of VTA neurons during alcohol withdrawal. Increasing cholesterol levels in the brain may be a novel avenue for therapeutic intervention to reverse detrimental effects of chronic alcohol exposure.

A dysregulated hypothalamic-pituitary-adrenal (HPA) axis has repeatedly been demonstrated to play a fundamental role in psychiatric disorders and suicide, yet the mechanisms underlying this dysregulation are not clear. Decreased expression of the glucocorticoid receptor (GR) gene, which is also susceptible to epigenetic modulation, is a strong indicator of impaired HPA axis control. In the context of teenage suicide-completers, we have systematically analyzed the 5'UTR of the GR gene to determine the expression levels of all GR exon-1 transcript variants and their epigenetic state. We also measured the expression and the epigenetic state of the FK506-binding protein 51 (FKBP5/FKBP51), an important modulator of GR activity. Furthermore, steady-state DNA methylation levels depend upon the interplay between enzymes that promote DNA methylation and demethylation activities, thus we analyzed DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and growth arrest- and DNA-damage-inducible proteins (GADD45). Focusing on both the prefrontal cortex (PFC) and hippocampus, our results show decreased expression in specific GR exon-1 variants and a strong correlation of DNA methylation changes with gene expression in the PFC. FKBP5 expression is also increased in both areas suggesting a decreased GR sensitivity to cortisol binding. We also identified aberrant expression of DNA methylating and demethylating enzymes in both brain regions. These findings enhance our understanding of the complex transcriptional regulation of GR, providing evidence of epigenetically mediated reprogramming of the GR gene, which could lead to possible epigenetic influences that result in lasting modifications underlying an individual's overall HPA axis response and resilience to stress.

Epigenetics in Psychiatry covers all major areas of psychiatry in which extensive epigenetic research has been performed, fully encompassing a diverse and maturing field, including drug addiction, bipolar disorder, epidemiology, cognitive disorders, and the uses of putative epigenetic-based psychotropic drugs. Uniquely, each chapter correlates epigenetics with relevant advances across genomics, transcriptomics, and proteomics. The book acts as a catalyst for further research in this potentially very important and useful area of psychiatry. The elucidation of basic principles of epigenetic biology points to the creation of more optimal and effective therapies for major classes of psychiatric disease. In this regard, epigenetic therapy, the use of drugs to correct epigenetic defects, may help in the pharmacotherapy of patients with these disorders. With time, such advances may eventually point to replacements for psychotropic drugs presently of symptomatic value and low efficacy. Moreover, there is evidence to suggest that other forms of treatment commonly used in the management of psychiatric disorders, like psychotherapy and electroconvulsive therapy, may also act by epigenetic mechanisms. * Chapters review fascinating new areas of research across neuronal stem cells, cognitive disorders, and transgenerational epigenetics through drug addiction* Relates broad advances in psychiatric epigenetics to a modern understanding of the genome, transcriptome, and protein* Catalyzes knowledge discovery in both basic epigenetic biology and clinical application as epigenetic targets for drug discovery

Positive effects of alcohol drinking such as anxiolysis and euphoria appear to be a crucial factor in the initiation and maintenance of alcohol use disorder (AUD). However, the mechanisms that lead from chromatin reorganization to transcriptomic changes after acute ethanol exposure remain unknown. Here, we used Assay for Transposase-Accessible Chromatin followed by high throughput sequencing (ATAC-seq) and RNA-seq to investigate epigenomic and transcriptomic changes that underlie anxiolytic effects of acute ethanol using an animal model. Analysis of ATAC-seq data revealed an overall open or permissive chromatin state that was associated with transcriptomic changes in the amygdala after acute ethanol exposure. We identified a candidate gene, Hif3a (Hypoxia-inducible factor 3, alpha subunit), that had ‘open’ chromatin regions (ATAC-seq peaks), associated with significantly increased active epigenetic histone acetylation marks and decreased DNA methylation at these regions. The mRNA levels of Hif3a were increased by acute ethanol exposure, but decreased in the amygdala during withdrawal after chronic ethanol exposure. Knockdown of Hif3a expression in the central nucleus of amygdala attenuated acute ethanol-induced increases in Hif3a mRNA levels and blocked anxiolysis in rats. These data indicate that chromatin accessibility and transcriptomic signatures in the amygdala after acute ethanol exposure underlie anxiolysis and possibly prime the chromatin for the development of AUD.

Background mGlu5 metabotropic glutamate receptors are considered as candidate drug targets in the treatment of “monogenic” forms of autism spectrum disorders (ASD), such as Fragile-X syndrome (FXS). However, despite promising preclinical data, clinical trials using mGlu5 receptor antagonists to treat FXS showed no beneficial effects. Objective Here, we studied the expression and function of mGlu5 receptors in the striatum of adult BTBR mice, which model idiopathic forms of ASD, and behavioral phenotype. Methods Behavioral tests were associated with biochemistry analysis including qPCR and western blot for mRNA and protein expression. In vivo analysis of polyphosphoinositides hydrolysis was performed to study the mGlu5-mediated intracellular signaling in the striatum of adult BTBR mice under basal conditions and after MTEP exposure. Results Expression of mGlu5 receptors and mGlu5 receptor-mediated polyphosphoinositides hydrolysis were considerably high in the striatum of BTBR mice, sensitive to MTEP treatment. Changes in the expression of genes encoding for proteins involved in excitatory and inhibitory neurotransmission and synaptic plasticity, including Fmr1, Dlg4, Shank3, Brd4, bdnf-exon IX, Mef2c, and Arc, GriA2, Glun1, Nr2A, and Grm1, Grm2, GriA1, and Gad1 were also found. Behaviorally, BTBR mice showed high repetitive stereotypical behaviors, including self-grooming and deficits in social interactions. Acute or repeated injections with MTEP reversed the stereotyped behavior and the social interaction deficit. Similar effects were observed with the NMDA receptor blockers MK-801 or ketamine. Conclusion These findings support a pivotal role of mGlu5 receptor abnormal expression and function in idiopathic ASD adult forms and unveil novel potential targets for therapy.

BACKGROUND:Alcohol use disorder (AUD) is a chronic relapsing brain disorder. GABAA receptor (GABAAR) subunits are a target for the pharmacological effects of alcohol. Neurosteroids play an important role in the fine-tuning of GABAAR function in the brain. Recently, we have shown that AUD is associated with changes in DNA methylation mechanisms. However, the role of DNA methylation in the regulation of neurosteroid biosynthesis and GABAergic neurotransmission in AUD patients remains under-investigated. METHODS:In a cohort of postmortem brains from 20 male controls and AUD patients, we investigated the expression of GABAAR subunits and neurosteroid biosynthetic enzymes and their regulation by DNA methylation mechanisms. Neurosteroid levels were quantified by gas chromatography-mass spectrometry. RESULTS:The α 2 subunit expression was reduced due to increased DNA methylation at the gene promoter region in the cerebellum of AUD patients, a brain area particularly sensitive to the effects of alcohol. Alcohol-induced alteration in GABAAR subunits was also observed in the prefrontal cortex. Neurosteroid biosynthesis was also affected with reduced cerebellar expression of the 18kDa translocator protein and 3α-hydroxysteroid dehydrogenase mRNAs. Notably, increased DNA methylation levels were observed at the promoter region of 3α-hydroxysteroid dehydrogenase. These changes were associated with markedly reduced levels of allopregnanolone and pregnanolone in the cerebellum. CONCLUSION:Given the key role of neurosteroids in modulating the strength of GABAAR-mediated inhibition, our data suggest that alcohol-induced impairments in GABAergic neurotransmission might be profoundly impacted by reduced neurosteroid biosynthesis most likely via DNA hypermethylation.

Laboratory models of schizophrenia are useful in the investigation of the role of epigenetic mechanisms to further understanding the pathophysiology of schizophrenia. Moreover, the successful design of rational pharmacotherapeutic strategies depends largely on testing hypotheses in vitro and in vivo in living animals. This chapter discusses laboratory epigenetic models of schizophrenia which include: hallucinogenic substance - induced phenotypes (HIS); the l-methionine-induced hypermethylation (MIH) model; the prenatal restraint stress (PRS) model in mice and rats; prenatal infection models; and cell culture-based in vitro models, namely, neuronal precursor cells (NT2 cells), and primary neuronal cultures.