Chaperone, Cochaperone, and Transcription Factor Proteins of the Glucocorticoid Receptor and Depression in Pregnancy Open Access

Katz, Elyse (2008)

Permanent URL: https://etd.library.emory.edu/concern/etds/6t053g02h?locale=en
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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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