Akbarian / Lubin Epigenetics and Neuroplasticity - Evidence and Debate

1. Auflage 2014
ISBN: 978-0-12-801085-3
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 128, 250 Seiten

Reihe: Progress in Molecular Biology and Translational Science

The 'epi-(Greek for 'over', 'above')genome', with its rich cache of highly regulated, structural modifications-including DNA methylation, histone modifications and histone variants-defines the moldings and three-dimensional structures of the genomic material inside the cell nucleus and serves, literally, as a molecular bridge linking the environment to the genetic materials in our brain cells. Due to technological and scientific advances in the field, the field of neuroepigenetics is currently one of the hottest topics in the basic and clinical neurosciences. The volume captures some of this vibrant and exciting new research, and conveys to the reader an up-to-date discussion on the role of epigenetics across the lifespan of the human brain in health and disease. - Topics cover the entire lifespan of the brain, from transgenerational epigenetics to neurodevelopmental disease to disorders of the aging brain. - All chapters are written with dual intent, to provide the reader with a timely update on the field, and a discussion of provocative or controversial findings in the field with the potential of great impact for future developments in the field.

Autoren/Hrsg.

Akbarian, Schahram

Lubin, Farah

Inhaltsverzeichnis

1;Front Cover;1
2;Epigenetics and Neuroplasticity-Evidence and Debate;4
3;Copyright;5
4;Contents;6
5;Contributors;10
6;Preface;12
7;Chapter One: The Epigenetic Basis of Memory Formation and Storage;16
7.1;1. Introduction to the Neurobiology of Learning and Memory;17
7.2;2. Epigenetic Mechanisms of Memory Consolidation;20
7.2.1;2.1. Histone acetylation;20
7.2.2;2.2. Histone methylation;21
7.2.3;2.3. Histone phosphorylation;23
7.2.4;2.4. Histone ubiquitination and sumoylation;24
7.2.5;2.5. DNA methylation;25
7.2.6;2.6. Summary of epigenetic regulation of memory consolidation;27
7.3;3. Epigenetic Mechanisms of Memory Reconsolidation;29
7.3.1;3.1. Histone modifications during memory reconsolidation;29
7.3.2;3.2. DNA methylation during memory reconsolidation;31
7.3.3;3.3. Epigenetic regulation of reconsolidation-dependent memory updating;31
7.3.4;3.4. Summary of epigenetic regulation of memory reconsolidation;32
7.4;4. Epigenetic Mechanisms of Memory Extinction;34
7.5;5. Future Directions and Conclusions;35
7.6;Acknowledgments;39
7.7;References;39
8;Chapter Two: Epigenetics in Posttraumatic Stress Disorder;44
8.1;1. Introduction;45
8.2;2. Epigenetic Evidences in PTSD;47
8.2.1;2.1. Methodological aspects and tissue specificity;48
8.2.2;2.2. Candidate gene approach in animals and humans;49
8.2.2.1;2.2.1. Focus on the HPA axis genes;49
8.2.2.2;2.2.2. Other stress-responsive genes;52
8.2.3;2.3. Genome-wide studies in animals and humans;53
8.3;3. Epigenetic Mechanisms in Gene by Environment Interactions in PTSD;55
8.4;4. Conclusions;57
8.5;References;58
9;Chapter Three: Histone-Mediated Epigenetics in Addiction;66
9.1;1. Introduction;67
9.2;2. General Overview of Histone-Mediated Epigenetics;68
9.3;3. Learning Processes Involved in the Development of Addiction;68
9.3.1;3.1. Initial establishment of drug-associated memories;69
9.3.2;3.2. Retrieval of drug-associated memories and extinction of drug-seeking behavior;70
9.4;4. Histone-Mediated Epigenetic Mechanisms;71
9.4.1;4.1. Repressive histone modifications;73
9.4.1.1;4.1.1. Methylation and phosphorylation;73
9.4.2;4.2. Active histone modifications;75
9.4.2.1;4.2.1. Methylation;75
9.4.2.2;4.2.2. Acetylation;75
9.4.2.3;4.2.3. Phosphorylation, ubiquitination, SUMOylation, and poly(ADP-ribosylation);76
9.4.3;4.3. Combinatorial modifications;78
9.5;5. Histone-Mediated Actions in Drug Addiction;78
9.5.1;5.1. Methylation and addiction;79
9.5.2;5.2. Acetylation and addiction;83
9.5.3;5.3. Combinatorial modifications and addiction;86
9.5.4;5.4. Summary of histone-mediated epigenetic regulation in addiction;87
9.6;6. Debates and Considerations;88
9.6.1;6.1. Are histone marks causal or correlational to downstream processes and do histone modifications change the structure a ...;88
9.6.2;6.2. What is the relation between memory at the cellular, organismal, and transgenerational levels?;89
9.6.3;6.3. What theoretical processes are altered by drugs that target histone modifications during treatment of addiction?;91
9.7;7. Considerations for Histone-Mediated Treatment of Addiction;93
9.8;Acknowledgments;94
9.9;References;94
10;Chapter Four: Modeling the Molecular Epigenetic Profile of Psychosis in Prenatally Stressed Mice;104
10.1;1. The Epigenetic Hypothesis of Psychosis;105
10.1.1;1.1. DNA methyltransferase;105
10.1.2;1.2. DNA demethylase;106
10.2;2. Prenatal or Early-Life Stress and Impaired Epigenetic Profile;109
10.3;3. The Epigenetic Modifications of GABAergic and Glutamatergic Genes Induced by Prenatal Stress in Mice Are Also Detected ...;110
10.4;4. PRS Mice Are a Promising Model for Studies of the Natural Course of SZ and BP Disorders;111
10.5;Acknowledgment;113
10.6;References;113
11;Chapter Five: Epigenetics of Depression;118
11.1;1. Introduction;119
11.1.1;1.1. Diagnosis of depression;119
11.1.2;1.2. Demographics of depression;120
11.1.2.1;1.2.1. Effect of gender and age on depression;120
11.1.2.2;1.2.2. Depression as a comorbid disorder;121
11.1.3;1.3. The etiology of depression;121
11.1.3.1;1.3.1. The neurotrophin hypothesis of MDD;122
11.1.3.2;1.3.2. Role of the HPA axis in depression;123
11.1.3.3;1.3.3. Animal models of stress and its role in depression;125
11.1.3.4;1.3.4. MDD is associated with structural changes in the brain;125
11.1.4;1.4. AD treatments;126
11.1.5;1.5. AD treatment response;126
11.2;2. Genetics of Major Depression;128
11.2.1;2.1. Candidate gene association studies;128
11.2.1.1;2.1.1. Genetic aspects of the serotonin transporter;129
11.2.2;2.2. Genome-wide association studies;131
11.2.3;2.3. Genetics of AD treatment response;131
11.3;3. Epigenetics of Major Depression;133
11.3.1;3.1. Environmental and developmental effects;133
11.3.2;3.2. Effects of early-life stress on epigenetic mechanisms;134
11.3.2.1;3.2.1. Intersection of stress and epigenetics;135
11.3.2.1.1;3.2.1.1. FK506-binding protein 5;135
11.3.2.1.2;3.2.1.2. Brain-derived neurotrophic factor;136
11.3.3;3.3. Depression-related genes: Epigenome scans;139
11.3.4;3.4. Epigenetic manipulation and depression (global vs. gene-specific effects);141
11.3.4.1;3.4.1. Caveats of epigenetic studies;141
11.3.5;3.5. Epigenetics of treatment response;142
11.3.6;3.6. Can epigenetic manipulation improve clinical outcome in major depression?;143
11.4;Acknowledgments and Disclosures;145
11.5;References;145
12;Chapter Six: Epigenetic Factors in Intellectual Disability: The Rubinstein-Taybi Syndrome as a Paradigm of Neurodevelopmen ...;154
12.1;1. Intellectual Disability and Chromatin-Modifying Enzymes;155
12.1.1;1.1. Developmental and adult component of IDDs;157
12.1.2;1.2. A network of epigenetic genes underlying IDDs;158
12.2;2. Molecular Genetics of RSTS;159
12.2.1;2.1. Rubinstein-Taybi syndrome;159
12.2.2;2.2. Phenotype-gene relationships;160
12.2.3;2.3. RSTS-related disorders;163
12.2.4;2.4. Function of the KAT3 enzymes CBP and p300;164
12.3;3. Lessons from Mouse Models;166
12.3.1;3.1. Different models address different questions;167
12.3.2;3.2. KAT3 proteins in neurodevelopment;170
12.3.3;3.3. Modeling syndromic manifestations;171
12.3.4;3.4. Cognitive impairments;172
12.3.5;3.5. Adult neurogenesis;174
12.3.6;3.6. Molecular etiology of RSTS;175
12.4;4. From Mouse Models to Patients: Therapy Prospects;176
12.4.1;4.1. HDAC inhibitors;176
12.4.2;4.2. PDE inhibitors;177
12.4.3;4.3. Environmental enrichment and occupational therapies;178
12.4.4;4.4. Adult neurogenesis as therapeutic target;179
12.5;5. Standing Questions and Controversies in RSTS Research;179
12.5.1;5.1. RSTS, a link between epigenetics and memory?;179
12.5.2;5.2. Do KAT3 deficiency and histone hypoacetylation cause neurodegeneration?;180
12.5.3;5.3. What is the relationship between transcription and CBP-dependent lysine acetylation?;181
12.6;6. Concluding Remarks;181
12.7;Acknowledgments;182
12.8;References;182
13;Chapter Seven: The Intergenerational Effects of Early Adversity;192
13.1;1. Introduction;192
13.2;2. Intergenerational Studies of Malnutrition: Human;193
13.3;3. Long-Term and Intergenerational Effects of Postnatal Malnutrition: The Barbados Nutrition Study;195
13.4;4. Intergenerational Studies of Malnutrition: Animal Studies;198
13.5;5. Intergenerational Studies of Early Adversity and Trauma: Human and Animal Studies;201
13.6;6. Other Intergenerational Studies: Chemical Exposures;203
13.7;7. Intergenerational Transmission: Epigenetic Mechanisms;204
13.8;8. Conclusion;207
13.9;Acknowledgments;207
13.10;References;207
14;Chapter Eight: The Future of Neuroepigenetics in the Human Brain;214
14.1;1. Introduction;215
14.1.1;1.1. Chromatin and epigenetic regulation: General principles;215
14.1.1.1;1.1.1. DNA (hydroxy)methylation;215
14.1.1.2;1.1.2. Histone modifications;216
14.1.1.3;1.1.3. Histone variants, chromatin remodeling, and nucleosome positioning;216
14.1.1.4;1.1.4. Chromatin-associated RNAs;217
14.1.1.5;1.1.5. Higher order chromatin;217
14.2;2. Challenges for Epigenetic Approaches in the (Human) Brain;218
14.2.1;2.1. Cellular specificity of epigenetic markings;218
14.2.2;2.2. With focus on the candidate gene approach, only few high-resolution epigenomic mappings;222
14.2.3;2.3. Higher order chromatin studies in the human brain;223
14.3;3. Evidence and Debate;225
14.3.1;3.1. Epigenetic markings in the brain: State or trait?;225
14.3.2;3.2. Mapping brain epigenomes from the culture dish?;227
14.3.3;3.3. Functional neuroepigenomics to inform disease-associated variants;230
14.4;4. Synopsis and Outlook;231
14.5;Conflict of Interest;234
14.6;Acknowledgment;234
14.7;References;234
15;Index;244
16;Color Plate;252

Leseproben

Chapter Two Epigenetics in Posttraumatic Stress Disorder
Carina Rampp*; Elisabeth B. Binder*,†; Nadine Provençal*    * Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
† Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA Abstract
Reported exposure to traumatic event is relatively common within the general population (40–90%), but only a fraction of individuals will develop posttraumatic stress disorder (PTSD). Indeed, the lifetime prevalence of PTSD is estimated to range between 7% and 12%. The factors influencing risk or resilience to PTSD after exposure to traumatic events are likely both environmental, such as type, timing, and extent of trauma, and genetic. Recently, epigenetic mechanisms have been implicated in mediating altered risk for PTSD as they can reflect both genetic and environmental influences. In this chapter, we describe the accumulating evidences for epigenetic factors in PTSD highlighting the importance of sensitive periods as well as methodological aspects such as tissue availabilities for such studies. We describe studies using a candidate gene approach focusing mainly on key players in the stress hormone regulation that show epigenetic alterations both in humans and in animal models for PTSD. We also summarize the results of epigenome-wide studies reporting associations with PTSD. For the above, we focus on one epigenetic mechanism, DNA methylation, as it is so far the best studied for this disorder. Finally, we describe how epigenetic mechanisms could be responsible for the long-lasting effects of gene–environment interactions observed in PTSD. Keywords Epigenetics DNA methylation PTSD Trauma Childhood maltreatment Gene × environment interaction 1 Introduction
Posttraumatic stress disorder (PTSD) is a psychiatric condition characterized by persistent symptoms of intrusive reexperiencing, avoidance, and autonomous–vegetative hyperarousal following exposure to a traumatic event. With a prevalence of around 5% in the general population and a lifetime prevalence ranging between 7% and 12%, it belongs to the most frequent psychiatric disorders whereat it is twice as common in women than in men.1 PTSD goes along with extensive suffering not only for the affected individual but also on a family and society level and constitutes a major burden for the health system. A traumatic event that can lead to PTSD is defined as an event that represents an intense threat for the own life, health, or physical integrity and goes along with feelings of strong fear and helplessness. Immediate witnessing of such an event can also lead to traumatization in the absence of personal victimization. PTSD can occur soon after the traumatic event or with delay. Dependent on the definition of trauma and the observed sample, a lifetime trauma incidence ranging between 40% and 90% has been reported in the general population.2,3 These high trauma exposure rates together with a relatively smaller prevalence of PTSD in the population indicate that trauma exposure does not necessarily lead to the development of PTSD. As generally observed in psychiatric disorders, trauma exposure has a stronger impact in more vulnerable individuals with a higher probability to develop a pathological phenotype.4,5 Indeed, different risk and resilience factors have been discussed for PTSD.4,6 One major risk factor that has been identified in PTSD is the type of the trauma itself. It could be shown, for example, that traumatic events caused directly by other individuals like physical violence or sexual assault involve a greater risk for PTSD than impersonal catastrophes like natural disasters.1,7 Here, among others, the amount of social support might play an important role, since it has been identified as a decisive protective factor in processing a traumatic experience.8 Often, the latter type of trauma affects many individuals at once and thus is accompanied by stronger social support, whereas the former mostly affects single individuals. In addition, the time of trauma during life plays a decisive role. Until two decades ago, the hypothesis that early-life trauma is associated with an increased risk of adult mood and anxiety disorders was supported largely by anecdotal reports inspired by psychoanalytic concepts of early critical periods of development.9 During the past years, an increasing amount of studies explored the consequences of early trauma on psychosocial and psychobiological development and clearly showed that the childhood period is a very sensitive period and that adverse experiences during that time coincide with a significantly higher risk for PTSD10–12 as well as other psychiatric disorders13–15 later in life. These observations are increasingly confirmed by neurobiological research that identified possible mechanisms by which early-life trauma can have long-lasting impact on pathophysiology of PTSD.16 The exploration of neurobiological and molecular principles underlying the susceptibility for PTSD and other affective disorders is currently a matter of intense research. The research for genetic variants mediating vulnerability for affective and anxiety disorders showed only limited success with no strong main genetic effects reported6,17 as is apparent from large genome-wide association studies for major depressive disorder (MDD).18–20 It is now well established that psychiatric phenotypes such as PTSD emerge from a complex interplay of genetic and environmental factors as well as epigenetic factors as it could be shown more recently.6 Epigenetic mechanisms, such as DNA methylation, not only program cell identity but also have been shown to play an important role in the biological response triggered by environmental changes.21 In recent years, the dynamic role of epigenetic regulation in response to the environment has become clear. In adaption to a stressor, an organism reacts with epigenetic changes that lead to changes in gene expression profiles and in consequence to alterations of biological pathways and of neuronal functioning.16 If the stressor overstrains capacities of an organism to adapt, it can lead to maladaptive changes and dysregulation of biological systems such as the hypothalamic–pituitary–adrenal (HPA) axis. Early trauma can engrave biological marks and exert a life-long impact on health and disease trajectories leading to a higher risk not only for psychiatric but also for internal diseases and an impaired immune function.22,23 This chapter will describe the accumulating evidences for epigenetic alterations in PTSD highlighting the importance of sensitive periods as well as methodological aspects such as tissue availabilities. It will highlight studies that used a candidate gene approach focusing mainly on HPA axis key players as well as epigenome-wide studies reporting DNA methylation alterations in humans and animal models for PTSD. Finally, it will also shed light onto how epigenetic mechanisms could be responsible for the long-lasting effects of gene–environment interactions observed in PTSD. 2 Epigenetic Evidences in PTSD
In addition to the DNA sequence that has been shown to regulate gene expression as well as to influence the risk for PTSD independently of the type of trauma exposure,24,25 epigenetic information is another layer of transcriptional regulation.26 The main functions of the epigenome are to regulate gene transcription and to compact the DNA into the cell nucleus. Several distinct epigenetic marks come together to achieve this, including DNA methylation and hydroxymethylation, histone modifications, ATP-dependent chromatin remodeling, and noncoding RNAs. These marks can prime not only current but also future gene expression and protein translation modifications making it a prime target to understand the effect of early trauma on the development of PTSD later in life. DNA methylation is a covalent modification of the cytosine residues that are located primarily but not exclusively at CpG dinucleotide sequences in mammals.27,28 Increased DNA methylation in the promoter region of a gene is usually associated with repressed gene expression29 as it can interfere with the binding of transcriptional enhancer complexes.30 Intragenic DNA methylation is also observed,27,31–33 and in contrast to promoter methylation, it is found to correlate both negatively and positively with gene expression34–37 as it can also interfere with the binding of transcriptional repressive complexes.38,39 To accurately maintain the DNA methylation profiles and prevent a drift in the DNA methylation pattern during the life course, several biochemical elements come into play. DNA methylation patterns are copied and maintained by DNA methyltransferases (DNMTs).40 Removal of methyl groups or DNA demethylation is achieved either through direct action of demethylases41 or through DNA excision/repair-based mechanisms42–47 involving intermediate steps, such as hydroxymethylation. As mentioned in Section 1, there is a growing body of evidence suggesting that in addition to the...