Lithium alters expression of RNAs in a type-specific manner in differentiated human neuroblastoma neuronal cultures, including specific genes involved in Alzheimer's disease.

Lithium (Li) is a medication long-used to treat bipolar disorder. It is currently under investigation for multiple nervous system disorders, including Alzheimer's disease (AD). While perturbation of RNA levels by Li has been previously reported, its effects on the whole transcriptome has been given little attention. We, therefore, sought to determine comprehensive effects of Li treatment on RNA levels. We cultured and differentiated human neuroblastoma (SK-N-SH) cells to neuronal cells with all-trans retinoic acid (ATRA). We exposed cultures for one week to lithium chloride or distilled water, extracted total RNA, depleted ribosomal RNA and performed whole-transcriptome RT-sequencing. We analyzed results by RNA length and type. We further analyzed expression and protein interaction networks between selected Li-altered protein-coding RNAs and common AD-associated gene products. Lithium changed expression of RNAs in both non-specific (inverse to sequence length) and specific (according to RNA type) fashions. The non-coding small nucleolar RNAs (snoRNAs) were subject to the greatest length-adjusted Li influence. When RNA length effects were taken into account, microRNAs as a group were significantly less likely to have had levels altered by Li treatment. Notably, several Li-influenced protein-coding RNAs were co-expressed or produced proteins that interacted with several common AD-associated genes and proteins. Lithium's modification of RNA levels depends on both RNA length and type. Li activity on snoRNA levels may pertain to bipolar disorders while Li modification of protein coding RNAs may be relevant to AD

Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients

Exosomes are cellular secretory vesicles containing microRNAs (miRNAs). Once secreted, exosomes are able to attach to recipient cells and release miRNAs potentially modulating the function of the recipient cell. We hypothesized that exosomal miRNA expression in brains of patients diagnosed with schizophrenia (SZ) and bipolar disorder (BD) might differ from controls, reflecting either disease-specific or common aberrations in SZ and BD patients. The sources of the analyzed samples included McLean 66 Cohort Collection (Harvard Brain Tissue Resource Center), BrainNet Europe II (BNE, a consortium of 18 brain banks across Europe) and Boston Medical Center (BMC). Exosomal miRNAs from frozen postmortem prefrontal cortices with well-preserved RNA were isolated and submitted to profiling by Luminex FLEXMAP 3D microfluidic device. Multiple statistical analyses of microarray data suggested that certain exosomal miRNAs were differentially expressed in SZ and BD subjects in comparison to controls. RT-PCR validation confirmed that two miRNAs, miR-497 in SZ samples and miR-29c in BD samples, have significantly increased expression when compared to control samples. These results warrant future studies to evaluate the potential of exosome-derived miRNAs to serve as biomarkers of SZ and BD

A Comprehensive Review on the Role of Non-Coding RNAs in the Pathophysiology of Bipolar Disorder

Aim: Bipolar disorder is a multifactorial disorder being linked with dysregulation of several genes. Among the recently acknowledged factors in the pathophysiology of bipolar disorder are non-coding RNAs (ncRNAs). Methods: We searched PubMed and Google Scholar databases to find studies that assessed the expression profile of miRNAs, lncRNAs and circRNAs in bipolar disorder. Results: Dysregulated ncRNAs in bipolar patients have been enriched in several neuron-related pathways such as GABAergic and glutamatergic synapses, morphine addiction pathway and redox modulation. Conclusion: Altered expression of these transcripts in bipolar disorder provides clues for identification of the pathogenesis of this disorder and design of targeted therapies for the treatment of patients. Keywords: bipolar disorder; circRNA; lncRNA; miRNA

Epigenetic management of major psychosis

Epigenetic mechanisms are thought to play a major role in the pathogenesis of the major psychoses (schizophrenia and bipolar disorder), and they may be the link between the environment and the genome in the pathogenesis of these disorders. This paper discusses the role of epigenetics in the management of major psychosis: (1) the role of epigenetic drugs in treating these disorders. At present, there are three categories of epigenetic drugs that are being actively investigated for their ability to treat psychosis: drugs inhibiting histone deacetylation; drugs decreasing DNA methylation; and drugs targeting microRNAs; and (2) the role of epigenetic mechanisms in electroconvulsive therapy in these disorders

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Novel mechanisms in depression: focus on telomere biology and epigenetic regulation

Depression is a complex disorder with an average lifetime prevalence from 11.1% to 14.6%. It causes serious disability and is a significant public health problem worldwide. The etiology of depression is heterogeneous and multifactorial. Traditionally, researchers have tried to investigate depression from biochemical, genetic, environmental and behavioral perspectives. Since few biomarkers are available, diagnosis and treatment are still based on clinical assessment and are far from satisfactory. In recent years, depression has been proposed to be a state of “accelerated biological aging”, with an increased risk of comorbidity with other ageing-related conditions such as diabetes, cardiovascular disease and dementia. There is accumulating evidence to support that depression itself is in fact a state that involves telomere dysfunction, a prominent feature in the ageing process. Epigenetic regulation, with an emerging role in a number of complex disorders, constitutes a fusion between the results of genetic, biochemical and environmental factors. The aim of this thesis was to investigate the pathophysiology of depression with a focus on mechanisms that are perturbed in telomere biology and epigenetic regulation. Specifically, in paper I and III: telomere length and the genetic variation in the hTERT gene were examined in relation to lithium treatment, to depression disorder and depressive episodes in bipolar disorder in human cohorts. In paper II, we used a genetic rat model of depression (FSL) to study hippocampal telomere length and telomerase activity, and investigated the mechanism of how lithium affects telomere length. The epigenetic mechanisms potentially involved in depression, specifically DNA methylation/hydroxymethylation and miRNAs were investigated in the prefrontal cortex region of the FSL rats in paper IV and V, respectively. The major finding from the thesis work includes 1) telomere lengths were decreased in saliva DNA from patients with adult depression 2) genetic variation in hTERT may influence the susceptibility to depression 3) telomeres and telomerase activity are dysfunctional in the hippocampus of the depressed FSL rats 4) long-term lithium treatment is associated with longer telomeres in bipolar disorder especially when therapeutically efficacious 5) lithium treatment may normalize hippocampal telomerase dysfunction through activation of β-catenin in the rat 6) sodium butyrate exerts antidepressant-like effect and the suggestive epigenetic effects may include DNA methylation changes that are mediated by the demethylation-facilitating enzyme TET1 in the rat 7) elevation of cytokine Il6 in the prefrontal cortex is associated with depression-like states and may involve disturbance in let-7 biogenesis in the rat 8) physical exercise appears to normalize Il6 and let-7 levels through regulatory processes upstream of primary miRNA transcription in the rat

MICRORNAS AS CANDIDATES FOR BIPOLAR DISORDER BIOMARKERS

Bipolar disorder (BD) is a common, recurring psychiatric illness with unknown pathogenesis. Much like other psychiatric diseases, BD suffers from the chronic lack of reliable biomarkers and innovative pharmacological interventions. Better characterization of clinical profiles, experimental medicine, genomic data mining, and the utilization of experimental models, including stem cell and genetically modified mice, are suggested ways forward. Environment, including early childhood experiences, has been documented to modulate the risk for the development of psychiatric disorders via epigenetic mechanisms. Key epigenetic regulators, microRNAs (miRNAs, miRs), govern normal neuronal functioning and show altered expression in diverse brain pathologies. We observed significant alterations of exosomal miR-29c levels in prefrontal cortex (Brodmann area 9, BA9) of BD patients. We also demonstrated that exosomes extracted from the anterior cingulate cortex (BA24), a crucial area for modulating emotional expression and affect, have increased levels of miR-149 in BD patients compared to controls. Because miR-149 has been shown to inhibit glial proliferation, we hypothesized that increased miR-149 expression in BA24-derived exosomes may be consistent with the previously reported reduced glial cell numbers in BA24 of patients diagnosed with familial BD. qPCR analysis of laser-microdissected neuronal and glial cells from BA24 cortical samples of BD patients verified that the glial, but not neuronal, population exhibits significantly increased miR-149 expression. These findings support neuron-glia interaction as a possible target mechanism in BD, implicated by others in neuroimaging, postmortem, and in vivo studies of the pathological changes mediated by glial cells

T cell deficits and overexpression of hepatocyte growth factor in anti-inflammatory circulating monocytes of middle-aged patients with bipolar disorder characterized by a high prevalence of the metabolic syndrome

Background: We previously reported T cell deficits and pro-inflammatory gene activation in circulating monocytes of two cohorts of bipolar disorder (BD) patients, a cohort of postpartum psychosis patients and in bipolar offspring. Pro-inflammatory gene activation occurred in two clusters of mutually correlating genes, cluster 1 for inflammation-related cytokines/factors, cluster 2 for motility, chemotaxis, and metabolic factors. Aim: To verify these cellular immune abnormalities in yet another cohort [the bipolar stress study (BiSS) cohort] of relative old (52 years, median) BD patients and to relate immune abnormalities to hair cortisol levels, measured in this cohort and representing long-term systemic cortisol levels, and to the presence of the metabolic syndrome (MetS), which was prevalent in 29% of the BiSS patients. Methods: Monocyte immune gene activation (quantitative polymerase chain reaction) and T cell deficits (fluorescence-activated cell sorting analysis) were determined in 97 well-controlled, largely euthymic BiSS BD patients. Monocyte genes included the cluster 1 and 2 genes, the genes for the glucocorticoid receptor (GR) a and GRß, and the gene for hepatocyte growth factor [HGF, a marker of monocyte-derived circulating angiogenic cells (CACs)]. CACs serve vessel repair. Abnormal numbers are found in patients with MetS and vascular damage. Results: As compared to healthy controls: (1) the pro-inflammatory cluster 1 genes were downregulated, and the GRa and the HGF gene were upregulated in the monocytes of the BiSS patients and (2) T cell deficits were shown (reduced numbers of lymphocytes in particular of T cells). Within the reduced T cell population, a shift had taken place in the T-helper populations: T-helper 17 and T-helper 2 increased and T regulatory cells decreased. Correlations between hair cortisol, the MetS, monocyte gene activation, and T cell deficits were not found. Conclusion: T cell defic

Bipolar disorder associated miR-499-5p controls dendritic development and Cav1.2 calcium channel activity

Affective disorders, such as Major depressive disorder (MDD) and Bipolar disorder (BD), are a group of neuropsychiatric disorders characterized by rofound mood dysregulations. They constitute leading causes of disability and mortality, with especially high rates of suicide. However, the lack of understanding of the molecular mechanisms that trigger the development of affective disorders imposes a challenge to the discovery of novel and effective pharmacotherapies. It is currently accepted that a complex interaction between genetic predisposition and exposure to environmental stressors, such as childhood maltreatment, is required for the development of these disorders. The underlying causes, however, are only poorly understood. One of the main research areas focuses on the dysregulation of synaptic and neural plasticity, based on reports of altered structural and functional brain connectivity in the prefrontal cortex (PFC) and hippocampus of patients. Genes that are involved in neuronal development and plasticity are regulated by microRNAs (miRNAs or miRs), a class of small non-coding RNAs. Importantly, dysregulated miRNA expression is frequently observed in the brain and blood of MDD and BD patients, providing a rationale to consider miRNAs as therapeutic tools and disease biomarkers. This study aimed to investigate how changes in gene expression mediated by miRNAs interact with negative life events, especially during early life, and result in aberrant neuroplastic alterations that increase the susceptibility to affective disorders. For this purpose, I characterized the change in miR-499-5p expression in the blood of affective disorder patients and healthy individuals at higher risk of developing an affective disorder due to a history of childhood maltreatment. I found a significant up-regulation in circulating miR-499-5p in patients and maltreated subjects. Consistently, I observed higher levels of miR-499-5p in the hippocampus of a rat model of early life adversity. To understand how the dysregulation of miR499-5p causes neuronal abnormalities, I used primary cultures from the rat hippocampus to overexpress miR-499-5p and evaluate changes in neuronal morphology and function. In rat hippocampal neurons, miR-499-5p targets the Cacnb2 gene, the auxiliary β-subunit of the L-type Cav1.2 calcium channels, and a risk gene for psychiatric disorders. Elevated miR-499-5p expression inhibited Cacnb2 mRNA translation, impaired dendritic development, and reduced Cav1.2 surface expression and activity. Importantly, overexpression of miR-499-5p in the hippocampus induced short-term memory impairments in the Cacna1c+/- rat model. Based on these results, I propose a mechanism of miRNA-mediated calcium dysfunction in BD susceptibility whereby early life stress induces the expression of miR-499-5p, which in turn impairs dendritic development by inhibiting the expression of an auxiliary subunit of Cav1.2 calcium channels. My work further suggests that the increased blood expression of miR-499-5p could potentially be used as a biomarker of BD development and disease progression

EPIGENETICS, RESILIENCE, COMORBIDITY AND TREATMENT OUTCOME

Personalized or precision medicine is a relatively new promising concept which is gaining momentum in all branches of medicine including psychiatry and neurology. Psychiatry and neurology are medical specialties dealing with diagnosis, prevention and treatment of brain disorders which are the main causes of years lived with disability worldwide as well as shortened life. Despite a huge progress in clinical psychopharmacology and neuropharmacology, the treatment outcome for many psychiatric disorders and neurologic diseases has remained unsatisfactory. With aging, comorbidities are more the rule, than an exception and may significantly influence on the final treatment outcome. Epigenetic modulation, resilience and life style are key determinants of the health and very important issues for understanding therapeutic mechanisms and responses. There is a hope that epigenetic profiling before treatment could be used in near future to increase the likelihood of good treatment response by selecting the appropriate medication. The aim of this paper is to offer an overview of the main aspects of epigenetic modulation, resilience and comorbidities and their role in developing the concept of personalized medicine. While waiting for more precise and reliable treatment guidelines it is possible to increase treatment effectiveness in psychiatry and neurology by enhancing individual resilience of patients and managing comorbidities properly