Chaperone, Cochaperone, and Transcription Factor Proteins of theGlucocorticoid Receptor and Depression in Pregnancy Pubblico
Katz, Elyse (2008)
Abstract
Depression during pregnancy is a major women's health concern. Similar to endocrine alterations observed in certain subtypes of depression, pregnancy induces dramatic changes in the function of the hypothalamus-pituitary adrenal (HPA)-axis, leading to elevated maternal levels of cortisol throughout gestation and increased glucocorticoid receptor (GR)-resistance. This dissertation investigates the hypothesis that sex-steroid-induced changes in the gene expression levels of proteins that regulate GR-mediated signaling adaptively alter GR-sensitivity in pregnancy. Dysfunction of these putative physiologic regulatory mechanisms may increase some women's risk for depression during by altering GR-sensitivity in a suboptimal manner.
Changes in peripheral-blood mRNA levels of 17 GR-associated proteins, serum levels of estrogen, progesterone, and cortisol over pregnancy, were compared in 202 women with and without depressive symptoms. In a subset of women, we characterized GR-sensitivity with an ex-vivo bioassay and observed an increase in GR-resistance with progressing gestation that was paralleled by a significant up-regulation of 8 of the investigated genes in non-medicated, non-depressed pregnant women. mRNA levels of 4 genes were significantly different between the depressed and non-depressed groups. mRNA levels of heat shock protein 70 and P23 significantly correlated with GR-sensitivity, possibly providing a mechanism for the observed changes in GR-sensitivity over pregnancy and with depressive symptoms.
Alterations in GR-sensitivity in depression during pregnancy may also be a molecular mechanism for the previously reported negative impact of maternal stress and depression in pregnancy on the health and well-being of offspring. Here, we show that maternal GR-sensitivity in pregnancy, genetic polymorphisms in FK506 binding protein 5 (FKBP5) impacting GR function, and gene expression of BAG1 and PPP5C associate with gestational duration. In addition, genetic polymorphisms in FKBP5 are associated with birth weight.
In summary, the results reported in this dissertation provide possible novel molecular mechanisms for the regulation of GR-sensitivity in pregnancy and show that depression during pregnancy associates with a dysfunction of pregnancy-related GR-chaperone up-regulation and steroid receptor sensitivity. Such dysfunction might have a direct impact on offspring and long-term consequences as prematurity and low birth weight have been linked to behavioral and metabolic disorders in childhood that can persist into adulthood.
Table of Contents
CHAPTER 1. INTRODUCTION 1
Overview 2
Depressive Symptoms during Pregnancy 3
The Endocrine System and Depression 14
Compensation for Endocrine Changes during Pregnancy and the Postpartum Period 17
Chaperones, Co-chaperones, and Transcription Factor Proteins in Psychiatry 23
Summary 25
References 27
CHAPTER 2. Expression of mRNA Encoding Chaperone, Co-chaperone, and Transcription Factor Proteins of the Glucocorticoid Receptor During
Pregnancy in a Psychiatric Population 36
Introduction 37
Methods 41
Results 47
Patient Demographics and Clinical Characteristics 47
Plasma levels of Cortisol, Estradiol, and Progesterone during Pregnancy in Depressed and Non-Depressed Women 49
GR sensitivity during Pregnancy 49
Gene Expression Changes during Pregnancy in Non-medicated, Non-depressed Women 53
Differential Regulation of Co-chaperone Genes in Non-medicated, Depressed and Non-depressed Women During Pregnancy 56
GR Sensitivity and Co-Chaperone Gene Expression 56
Cortisol, Estradiol and Progesterone Levels and Gene Expression in Pregnancy 59
Discussion 59
GR Function during Pregnancy 61
GR Function in Peripartum Depression 63
Potential mechanisms for depressive symptom-related differences in chaperone and GR function 65
Conclusions 66
REFERENCES 68
CHAPTER 3. MODULATORS OF THE GLUCOCORTICOID RECEPTOR, GLUCOCORTICOID RECEPTOR FUNCTION, AND NEONATAL OUTCOMES 73
Introduction 74
Methods 76
Results 80
Gene expression and EGA at Delivery 80
Gene expression and Birth Weight 80
SNPS and EGA at Delivery 82
SNPS and Birth Weight 83
GR sensitivity and EGA at delivery 83
Depressive Symptoms and Birth Outcomes 85
Discussion 86
References 91
CHAPTER 4. DISCUSSION 94
SUMMARY OF FINDINGS AND DISCUSSION 95
LIMITATIONS OF THE STUDY SAMPLE 99
PERIPHERAL BLOOD MONOCYTES (PBMCs) AND BRAIN FUNCTION 100
FUTURE DIRECTIONS 102
Molecular Predictors of Relapse of Depression Symptoms 102
Steroid Hormones, Brain Structure, and Function 104
REFERENCES 106
APPENDIX A. Standardization of gene expression measures in paxgene and tempus rna tubes 108
BACKGROUND 109
METHODS 109
RESULTS 111
CONCLUSION 116
REFERENCES 117
APPENDIX B. Modified Protocol for mRNA Extraction from PAXgene and Tempus RNA Tubes 118
APPENDIX C. FIGURES FROM DISCUSSION (CHAPTER 4) 123
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