Transcriptional regulation of Homer1a during Pavlovian Fear Conditioning Open Access

Mahan, Amy Louise (2011)

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The consolidation of fear conditioning involves upregulation of genes necessary for long-
term memory formation. We examined whether homer1a, which is required for memory
formation, is downstream of BDNF - TrkB activation. In chapter 3 we demonstrate that homer1a
mRNA 1) increases after fear conditioning in vivo within both amygdala and hippocampus, 2)
increases after BDNF application to primary hippocampal and amygdala cultures in vitro, 3) these
increases are dependent on transcription and MAPK signaling, and 4) we demonstrate that a trkB
agonist, 7,8-DHF enhances long-term memory for Pavlovian fear conditioning in vivo as well as
increasing expression level of homer1a in vitro, and that inhibiting trkB signaling impairs
homer1a expression during Pavlovian conditioning in the amygdala and hippocampus. In chapter 4
we demonstrate that 1) Pavlovian fear conditioning induces distinct modifications of histones
bound to the Homer1 promoter; 2) BDNF induced plasticity produced similar modifications of
histones bound to the Homer1a promoter in primary amygdala and hippocampal cell culture; and
3) Sodium Butyrate, a histone deacetylase inhibitor, enhanced contextual fear memories,
hippocampal mRNA expression and hippocampal H3 acetylation around the Homer1 promoter. In
Chapter 5 we demonstrate that homer1a gene transcription and changes in histone modifications
during fear conditioning are mediated through CREB binding around the Homer1 promoter by: 1)
demonstrating that CREB and CBP are increasingly bound to the Homer1 promoter after fear
conditioning and 2) that inhibiting CREB inhibits homer1a expression, CBP binding and histone
modifications after fear conditioning. Together these data suggest that CREB and CBP are critical
for regulation of homer1a expression, in part via modulation of histone acetylation regulating
chromatin containing the homer1 gene. This body of work provides evidence for dynamic
regulation of homer1a following BDNF-induced plasticity or during a BDNF-dependent learning

Transcriptional Regulation of Homer1a During Pavlovian Fear Conditioning
B.S., Trinity University
Advisor: Kerry J. Ressler, M.D., Ph.D.
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate
Division of Biological and Biomedical Sciences

Table of Contents

Table of Contents

Chapter 1: Introduction Fear Conditioning, Synaptic Plasticity, and the Amygdala:

Implications for Posttraumatic Stress Disorder 1

1.1 Abstract 2

1.2 Introduction 2

1.3 Pavlovian fear conditioning as a model for understanding the underlying

mechanisms of pathological fear responses 4

1.4 Neurotrophic mechanisms of synaptic plasticity in fear conditioning 7

1.5 GABAergic Inhibitory Regulation of Neuronal Circuits in Fear Conditioning 13

1.6 Glutamatergic Signaling in Fear conditioning 17

1.7 Conclusions 20

1.8 Figures 22

1.9 References 38

Chapter 2 The Role of Homer1 in Posttraumatic Stress Disorder and Psychiatric Disease 56

2.1 Homer1 genetic association studies in Psychiatric Disease 57

2.2 The Homer1 gene family: Structure and Function 59

2.3 Role of Homer1a in animal models of psychiatry 62

2.4 Homer1a and Pavlovian Fear conditioning 64

2.5 Conclusions 66

2.6 Figures 67

2.7 References 71

Chapter 3 Homer 1a transcription is upregulated by Pavlovian Fear conditioning

and BDNF-TrkB signaling in the amygdala and Hippocampus 81

3.1 Abstract 82

3.2 Introduction 82

3.3 Methods 84

3.4 Results 88

3.6 Discussion 91

3.7 Figures 95

3.8 References 108

Chapter 4 Epigentetic Regulation of Homer1a during Pavlovian fear conditioning and BDNF induced plasticity 111

4.1 Introduction 112

4.2 Methods 113

4.3 Results 118

4.4 Discussion 119

4.5 Figures 123

4.6 References 127

Chapter 5 CREB and CBP Regulation of Homer1a during Pavlovian

fear conditioning and BDNF 129

5.1 Abstract 130

5.2 Introduction 130

5.3 Methods 133

5.4 Results 138

5.5 Discussion 141

5.6 Figures 144

5.7 References 160

Chapter 6 General Discussion/Conclusion: Summary of Findings, Future Directions, and Clinical Implications 163

6.1 Summary of Findings 164

6.2 Limitations of Findings 164

6.3 Epigenetics and Pavlovian Fear Conditioning 167

6.4 Homer1a and Pavlovian Fear conditioning 169

6.6 Homer1a in PTSD 171

6.7 Future Directions 171

6.7 Figures 173

6.8 References 175

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