Developmental mechanisms and experimental models to understand forebrain malformative diseases

The development of the central nervous system can be divided into a number of phases, each of which can be subject of genetic or epigenetic alterations that may originate particular developmental disorders. In recent years, much progress has been made in elucidating the molecular and cellular mechanisms by which the vertebrate forebrain develops. Therefore, our understanding of major developmental brain disorders such as cortical malformations and neuronal migration disorders has significantly increased. In this review, we will describe the major stages in forebrain morphogenesis and regionalization, with special emphasis on developmental molecular mechanisms derailing telencephalic development with subsequent damage to cortical function. Because animal models, mainly mouse, have been fundamental for this progress, we will also describe some characteristic mouse models that have been capital to explore these molecular mechanisms of malformative diseases of the human brain. Although most of the genes involved in the regulation of basic developmental processes are conserved among vertebrates, the extrapolation of mouse data to corresponding gene expression and function in humans needs careful individual analysis in each functional system.     

Developmental mechanisms and experimental models to understand forebrain malformative diseases

The development of the central nervous system can be divided into a number of phases, each of which can be subject of genetic or epigenetic alterations that may originate particular developmental disorders. In recent years, much progress has been made in elucidating the molecular and cellular mechanisms by which the vertebrate forebrain develops. Therefore, our understanding of major developmental brain disorders such as cortical malformations and neuronal migration disorders has significantly increased. In this review, we will describe the major stages in forebrain morphogenesis and regionalization, with special emphasis on developmental molecular mechanisms derailing telencephalic development with subsequent damage to cortical function. Because animal models, mainly mouse, have been fundamental for this progress, we will also describe some characteristic mouse models that have been capital to explore these molecular mechanisms of malformative diseases of the human brain. Although most of the genes involved in the regulation of basic developmental processes are conserved among vertebrates, the extrapolation of mouse data to corresponding gene expression and function in humans needs careful individual analysis in each functional system.     

The Regulation of GluN2A by Endogenous and Exogenous Regulators in the Central Nervous System

The NMDA receptor is the most widely studied ionotropic glutamate receptor, and it is central to many physiological and pathophysiological processes in the central nervous system. GluN2A is one of the two main types of GluN2 NMDA receptor subunits in the forebrain. The proper activity of GluN2A is important to brain function, as the abnormal regulation of GluN2A may induce some neuropsychiatric disorders. This review will examine the regulation of GluN2A by endogenous and exogenous regulators in the central nervous system.     

Emerging roles of epigenetic mechanisms in Parkinson’s disease

Epigenetic mechanisms have emerged as important components of a variety of human diseases, including cancer and central nervous system disorders. Despite recent studies highlighting the role of epigenetic mechanisms in several neurodegenerative and neuropsychiatric disorders, to date, there has been a paucity of studies exploring the role of epigenetic factors in Parkinson’s disease (PD). PD is a progressive neurological disorder with characteristic motor and non-motor symptoms, including a range of neuropsychiatric features, for which neither preventative nor effective long-term treatment strategies are available. It is one of the most common neurodegenerative disorders and the second most prevalent after Alzheimer’s disease. In this review, we present several lines of evidence suggesting that epigenetic factors may play an important role in the pathogenesis of PD and propose on this basis a framework to guide future investigations into epigenetic mechanisms and systems biology of PD. These notions, together with technical advances in the ability to perform genome-wide analysis of epigenomic states, and newly available small-molecule probes targeting chromatin-modifying enzymes, may help design new treatment strategies for PD and other human diseases involving epigenetic dysregulation.     

EWSR1, a multifunctional protein,regulates cellular function and aging via genetic and epigenetic pathways

Ewing's sarcoma (EWS) is a bone cancer arising predominantly in young children. EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutations of EWSR1 genes are known to be associated with central nervous system disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Otherwise, EWSR1 plays epigenetic roles in gene expression, RNA processing, and cellular signal transduction. Interestingly, EWSR1 controls micro RNA (miRNA) levels via Drosha, leading to autophagy dysfunction and impaired dermal development. Ewsr1 deficiency also leads to premature senescence of blood cells and gamete cells with a high rate of apoptosis due to the abnormal meiosis. Despite these roles of EWSR1 in various cellular functions, the exact mechanisms are not yet understood. In this context, the current review overviews a large body of evidence and discusses on what EWSR1 genetic mutations are associated with brain diseases and on how EWSR1 modulates cellular function via the epigenetic pathway. This will provide a better understanding of bona fide roles of EWSR1 in aging and its association with brain disorders.     

Biological factors underlying sex differences in neurological disorders

The prevalence, age of onset, pathophysiology, and symptomatology of many neurological and neuropsychiatric conditions differ significantly between males and females. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and autism spectrum disorders (ASD). Until recently, these sex differences have been explained solely by the neuroprotective actions of sex hormones in females. Emerging evidence however indicates that the sex chromosome genes (i.e. X- and Y-linked genes) also contribute to brain sex differences. In particular, the Y-chromosome gene, SRY (Sex-determining Region on the Y chromosome) is an interesting candidate as it is expressed in dopamine-abundant brain regions, where it regulates dopamine biosynthesis and dopamine-mediated functions such as voluntary movement in males. Furthermore, SRY expression is dysregulated in a toxin-induced model of PD, suggesting a role for SRY in the pathogenesis of dopamine cells. Taken together, these studies highlight the importance of understanding the interplay between sex-specific hormones and sex-specific genes in healthy and diseased brain. In particular, better understanding of regulation and function of SRY in the male brain could provide entirely novel and important insights into genetic factors involved in the susceptibility of men to neurological disorders, as well as development of novel sex-specific therapies.     

Brain Banks Spur New Frontiers in Neuropsychiatric Research and Strategies for Analysis and Validation

Neuropsychiatric disorders affect hundreds of millions of patients and families worldwide. To decode the molecular framework of these diseases, many studies use human postmortem brain samples. These studies reveal brain-specific genetic and epigenetic patterns via high-throughput sequencing technologies. Identifying best practices for the collection of postmortem brain samples, analyzing such large amounts of sequencing data, and interpreting these results are critical to advance neuropsychiatry. We provide an overview of human brain banks worldwide, including progress in China, highlighting some well-known projects using human postmortem brain samples to understand molecular regulation in both normal brains and those with neuropsychiatric disorders. Finally, we discuss future research strategies, as well as state-of-the-art statistical and experimental methods that are drawn upon brain bank resources to improve our understanding of the agents of neuropsychiatric disorders.     

肠道菌群与神经精神疾病

人体肠道中存在着数量庞大和种类繁多的细菌,这些细菌及其代谢产物在代谢、免疫、内分泌、神经等方面起着重要作用,对于人类的健康有着重要影响。近年来越来越多的研究表明,正常的肠道菌群在维持大脑的发育与功能方面扮演着重要角色,而肠道菌群的失调与一些神经精神疾病密切相关,例如帕金森症、多发性硬化、抑郁、自闭症等。本文就肠道菌群与神经精神疾病的关系作一综述。     

Epigenetic and genetic variation at the IGF2/H19 imprinting control region on 11p15.5 is associated with cerebellum weight

IGF2 is a paternally expressed imprinted gene with an important role in development and brain function. Allele-specific expression of IGF2 is regulated by DNA methylation at three differentially methylated regions (DMRs) spanning the IGF2/H19 domain on human 11p15.5. We have comprehensively assessed DNA methylation and genotype across the three DMRs and the H19 promoter using tissue from a unique collection of well-characterized and neuropathologically-dissected post-mortem human cerebellum samples (n = 106) and frontal cortex samples (n = 51). We show that DNA methylation, particularly in the vicinity of a key CTCF-binding site (CTCF3) in the imprinting control region (ICR) upstream of H19, is strongly correlated with cerebellum weight. DNA methylation at CTCF3 uniquely explains ∼25% of the variance in cerebellum weight. In addition, we report that genetic variation in this ICR is strongly associated with cerebellum weight in a parental-origin specific manner, with maternally-inherited alleles associated with a 16% increase in cerebellum weight compared with paternally-inherited alleles. Given the link between structural brain abnormalities and neuropsychiatric disease, an understanding of the epigenetic and parent-of-origin specific genetic factors associated with brain morphology provides important clues about the etiology of disorders such as schizophrenia and autism.Key words: epigenetic, DNA methylation, genomic imprinting, cerebellum, IGF2, H19, brain, expression, frontal cortex, genetic, single nucleotide polymorphism     

Epigenetics in the nervous system: An overview of its essential role

The role that epigenetic mechanisms play in phenomena such as cellular differentiation during embryonic development, X chromosome inactivation, and cancers is well-characterized. Epigenetic mechanisms have been implicated to be the mediators of several functions in the nervous system such as in neuronal-glial differentiation, adult neurogenesis, the modulation of neural behavior and neural plasticity, and also in higher brain functions like cognition and memory. Its particular role in explaining the importance of early life/social experiences on adult behavioral patterns has caught the attention of scientists and has spawned the exciting new field of behavioral epigenetics which may hold the key to explaining many complex behavioral paradigms. Epigenetic deregulation is known to be central in the etiology of several neuropsychiatric disorders which underscore the importance of understanding these mechanisms more thoroughly to elucidate novel and effective therapeutic approaches. In this review we present an overview of the findings which point to the essential role played by epigenetics in the vertebrate nervous system.     

Analysis of free D-serine in mammals and its biological relevance

D-Serine is a unique endogenous substance enriched in the brain at the exceptionally high concentrations as a free D-amino acid in mammals throughout their life. Peripheral tissues and blood contain low or trace levels of the D-amino acid. In the nervous systems, D-serine appears to act as an intrinsic coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDA receptor) based upon the following characteristics: (i) D-serine stereoselectively binds to and stimulates the glycine-regulatory site of the NMDA receptor consisting of GRIN1/GRIN2 subunits more potently than glycine with an affinity and ED50 at high nanomolar ranges, (ii) the selective elimination of D-serine in brain tissues attenuates the NMDA receptor functions, indicating an indispensable role in physiological activation of the glutamate receptor, and (iii) the distribution of D-serine is uneven and closely correlated with that of the binding densities of the various NMDA receptor sites, and especially of the GRIN2B subunit in the brain. Moreover, d-serine exerts substantial influence on the GRIN1/GRIN3-NMDA and δ2 glutamate receptor. In the brain and retina, metabolic processes of D-serine, such as biosynthesis, extracellular release, uptake, and degradation, are observed and some candidate molecules that mediate these processes have been isolated. The fact that the mode of extracellular release of D-serine in the brain differs from that of classical neurotransmitters is likely to be related to the detection of D-serine in both glial cells and neurons, suggesting that d-serine signals could be required for the glia-synapse interaction. Moreover, the findings from the basic experiments and clinical observations support the views that the signaling system of endogenous free D-serine plays important roles, at least, through the action on the NMDA receptors in the brain wiring development and the regulation of higher brain functions, including cognitive, emotional and sensorimotor function. Based upon these data, aberrant D-serine-NMDA receptor interactions have been considered to be involved in the pathophysiology of a variety of neuropsychiatric disorders including schizophrenia and ischemic neuronal cell death. The molecular and cellular mechanisms for regulating the D-serine signals in the nervous system are, therefore, suitable targets for studies aiming to elucidate the causes of neuropsychiatric disorders and for the development of new treatments for intractable neuropsychiatric symptoms.     

Single Cell Genomics of the Brain: Focus on Neuronal Diversity and Neuropsychiatric Diseases

Single cell genomics has made increasingly significant contributions to our understanding of the role that somatic genome variations play in human neuronal diversity and brain diseases. Studying intercellular genome and epigenome variations has provided new clues to the delineation of molecular mechanisms that regulate development, function and plasticity of the human central nervous system (CNS). It has been shown that changes of genomic content and epigenetic profiling at single cell level are involved in the pathogenesis of neuropsychiatric diseases (schizophrenia, mental retardation (intellectual/leaning disability), autism, Alzheimer’s disease etc.). Additionally, several brain diseases were found to be associated with genome and chromosome instability (copy number variations, aneuploidy) variably affecting cell populations of the human CNS. The present review focuses on the latest advances of single cell genomics, which have led to a better understanding of molecular mechanisms of neuronal diversity and neuropsychiatric diseases, in the light of dynamically developing fields of systems biology and “omics”.     

Frank A. Beach Award: Programming of neuroendocrine function by early-life experience: A critical role for the immune system

Many neuropsychiatric disorders are associated with a strong dysregulation of the immune system, and several have a striking etiology in development as well. Our recent evidence using a rodent model of neonatal Escherichia coli infection has revealed novel insight into the mechanisms underlying cognitive deficits in adulthood, and suggests that the early-life immune history of an individual may be critical to understanding the relative risk of developing later-life mental health disorders in humans. A single neonatal infection programs the function of immune cells within the brain, called microglia, for the life of the rodent such that an adult immune challenge results in exaggerated cytokine production within the brain and associated cognitive deficits. I describe the important role of the immune system, notably microglia, during brain development, and discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, and cognition.