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Epigenetic Programming by Prenatal Stress in Female Serotonin Transporter Deficient Mice

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Epigenetic Programming by Prenatal Stress in Female Serotonin Transporter Deficient Mice Epigenetic programming by prenatal stress in female serotonin transporter deficient mice Epigenetische Programmierung durch Pränatalstress in weiblichen Serotonintransporter-defizienten Mäusen Doctoral thesis for a doctoral degree at the Graduate School of Life Sciences, Julius-Maximilians-Universität Würzburg, Section Neuroscience Submitted by Karla-Gerlinde Schraut from Timişoara, România Würzburg, 2015 Submitted on: ............................................................................. Members of the Promotionskomitee: Chairperson: Prof. Dr. Thomas Dandekar Primary Supervisor: Prof. Dr. Klaus-Peter Lesch Supervisor (Second): Prof. Dr. Charlotte Förster Supervisor (Third): Dr. Daniel van den Hove Date of Public Defense: ............................................................... Date of Receipt of Certificates: .................................................... Table of Contents Table of Contents ................................................................................................................................ I Abbreviations ..................................................................................................................................... V Summary…………………………………………………………………………………………………..XI Zusammenfassung ........................................................................................................................... XV 1. General introduction ................................................................................................... 1 1.1. Variation in the serotonin transporter gene – from mice and men ................................ 1 1.1.1. Anatomy and function of the serotonergic system .............................................. 1 1.1.2. 5-HT synthesis and metabolism ................................................................................. 3 1.1.3. Dysfunction of the serotonergic system in psychiatric disorders ........................ 3 1.1.4. Genetic variation in the 5-HTT gene ........................................................................ 4 1.1.5. 5-HTT deficient mice ................................................................................................... 6 1.2. Prenatal stress ............................................................................................................................ 9 1.2.1. Early environment might shape adult phenotypes .............................................. 9 1.2.2. What do we know about the effects of prenatal stress? ..................................10 1.2.3. The HPA axis ...............................................................................................................13 1.2.4. Stress hormones during pregnancy .......................................................................16 1.3. Epigenetics ..............................................................................................................................19 1.3.1. DNA methylation and the epigenome .................................................................19 1.3.2. Functional molecular mechanisms of DNA methylation and demethylation .....................................................................................................................................21 1.3.3. DNA methylation patterns across the lifespan ....................................................23 2. Project 1 – The effects of 5-Htt genotype and PS on hippocampal gene expression and DNA methylation ...........................................................................27 2.1. Introduction .............................................................................................................................27 2.2. Methods and Materials .........................................................................................................29 2.2.1. Animals and ethics ...................................................................................................29 I 2.2.2. Behavioral testing .....................................................................................................29 2.2.3. Gene expression analysis .........................................................................................31 2.2.4. DNA methylation analysis ........................................................................................34 2.2.5. Statistics .......................................................................................................................39 2.3. Results .......................................................................................................................................41 2.3.1. Expression of myelin-associated genes.................................................................41 2.3.2. Gene expression of major myelin proteins and transcription factors in hippocampus and amygdala assessed by RT-qPCR .........................................47 2.3.3. DNA methylation .......................................................................................................52 2.4. Discussion .................................................................................................................................69 2.4.1. Effects of 5-Htt genotype and PS on DNA methylation .....................................69 2.4.2. Genes affected both on expression and DNA methylation level....................70 2.4.3. 5-Htt genotype dependent changes in expression of myelin-associated genes and in Mbp methylation induced by PS ..................................................72 2.4.4. On the (missing) relationship of DNA methylation and expression ..................77 2.4.5. Study limitations .........................................................................................................79 2.4.6. Conclusion and outlook ..........................................................................................80 3. Project 2 – Resilience towards PS in 5-Htt deficient female mice .....................83 3.1. Introduction .............................................................................................................................83 3.2. Methods and Materials .........................................................................................................85 3.2.1. Animals and ethics ...................................................................................................85 3.2.2. Behavioral testing .....................................................................................................85 3.2.3. Physiological parameters ........................................................................................87 3.2.4. Processing of brain tissue .........................................................................................88 3.2.5. Gene expression analysis .........................................................................................89 3.2.6. Statistics .......................................................................................................................90 3.3. Results .......................................................................................................................................91 3.3.1. Dam and pups weight .............................................................................................91 3.3.2. Offspring behavior ....................................................................................................91 3.3.3. Physiological parameters ........................................................................................97 II 3.3.4. Transcriptome analysis using mRNA sequencing ................................................98 3.4. Discussion .............................................................................................................................. 157 3.4.1. Behavioral effects of 5-Htt x PS interaction ....................................................... 157 3.4.2. Hippocampal gene expression profiles of 5-Htt+/- mice exposed to PS ..... 159 3.4.3. Altered expression of genes associated with myelination and oligodendrocytes due to 5-Htt x PS interaction ............................................... 163 3.4.4. Manipulation at the 5-Htt locus affected expression of numerous genes on chr 11 ....................................................................................................................... 169 3.4.5. Pathways affected in social, but not in unsocial, 5-Htt+/- mice exposed to PS .................................................................................................................................. 173 3.4.6. Study limitations and methodological issues .................................................... 176 3.4.7. Conclusion and outlook ....................................................................................... 177 4. Appendix .................................................................................................................. 180 4.1. Appendix Tables (see enclosed DVD) ............................................................................. 180 4.2. References ............................................................................................................................ 181 4.3. List of figures ......................................................................................................................... 202 4.4. List of tables .......................................................................................................................... 204 4.5. Curriculum vitae .................................................................................................................
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