Physiological Effects of Estradiol in the Mouse Hippocampal Formation Joanna L

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Physiological Effects of Estradiol in the Mouse Hippocampal Formation Joanna L Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2009 Physiological Effects of Estradiol in the Mouse Hippocampal Formation Joanna L. Spencer Follow this and additional works at: http://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons Recommended Citation Spencer, Joanna L., "Physiological Effects of Estradiol in the Mouse Hippocampal Formation" (2009). Student Theses and Dissertations. Paper 142. This Thesis is brought to you for free and open access by Digital Commons @ RU. It has been accepted for inclusion in Student Theses and Dissertations by an authorized administrator of Digital Commons @ RU. For more information, please contact [email protected]. PHYSIOLOGICAL EFFECTS OF ESTRADIOL IN THE MOUSE HIPPOCAMPAL FORMATION A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Joanna L. Spencer June 2009 © Copyright by Joanna L. Spencer 2009 PHYSIOLOGICAL EFFECTS OF ESTRADIOL IN THE MOUSE HIPPOCAMPAL FORMATION Joanna L. Spencer, Ph.D. The Rockefeller University 2009 At several points in a woman’s life, changes in circulating estradiol are associated with disturbances in mood and cognitive function. To determine the biological basis of these behavioral changes, researchers have concentrated on the hippocampal formation, a medial temporal lobe structure involved in the regulation of mood and cognition in humans. It is now clear that estradiol increases the substrates of hippocampal synaptic plasticity, including dendritic spine density, synapse density, and synaptic protein expression. In some cases, these changes are associated with alterations in mood and hippocampal-dependent learning and memory. The upstream mediators of these estradiol effects remain unknown, but likely candidates may be inferred from known regulators of hippocampal synaptic plasticity and estradiol effects in other tissues. This thesis explored estradiol activation of two of these candidates, PI3 kinase/Akt and brain-derived neurotrophic factor (BDNF), in the dorsal hippocampus of female mice. In naturally cycling and ovariectomized female mice, estradiol increased hippocampal Akt and BDNF signaling as determined by immunocytochemistry and in situ hybridization. These effects were associated with changes in synaptic protein expression, and required specific estrogen receptor isoforms, as demonstrated using estrogen receptor knockout mice. Immuno-electron microscopy revealed that estradiol specifically increased signaling through presynaptic TrkB receptors in Schaffer collateral and mossy fiber axons. Estradiol effects on Akt signaling were associated with changes in spatial memory ability, and were profoundly altered in mice expressing the BDNF variant Val66Met. This study therefore identifies Akt and BDNF signaling as important upstream pathways in the control of hippocampal function by ovarian steroids in vivo. Circulating estradiol activates Akt rapidly through a BDNF-dependent mechanism, and increases expression of BDNF more slowly, leading to increased activation of the BDNF receptor TrkB. After activation, Akt and TrkB may participate in estradiol regulation of spine synapse density and hippocampal cell excitability. Future studies should aim to understand the specific role of Akt and BDNF in estradiol modulation of hippocampal function and behavior. In loving memory of my mother Dr. Susan Spencer, M.D. iii Acknowledgments On my first day of graduate school, the day that I would turn in my written thesis and successfully defend my own ideas seemed impossibly remote. The process seemed foreign and undefined, and I did not know which specific exercises would help me achieve scientific competence in the eyes of my lab and the outside world. The integral people to this process, who helped me to achieve this end, are many. The other students and post docs in the McEwen lab drew me in to the fold with their friendliness, their humor, and a constant buzz of scientific curiousity. Dr. Elizabeth Waters served as my direct mentor from day one, and remained the most important person in my daily laboratory life even as I gained my independence. My parents, Drs. Susan and Dennis Spencer, are role model physician-scientists. Without their emotional and material support, I would not have made it this far. My sister, Dr. Andrea Spencer, endured with great sympathy years of short phone calls and infrequent visits dictated by one experiment or another. Dr. Charles Greer’s love of neuroscience motivated me to go down this path, and he guided me with his wise words on things personal and professional. Dr. Michael Caplan introduced me to the lab when I was a freshman in college, and he and Charlie together can claim responsibility for iv my decision to pursue an MD/PhD degree...so far so good, guys! My partner Yaniv patiently weathered the daily stressors of scientific life along with me, and perhaps gained more of a scientific education than he bargained for along the way. These studies would not have been possible without the help of several collaborators and advisors, including Victoria Luine from Hunter College, Donna Korol from the University of Illinois, Moses Chao from New York University, Sonoko Ogawa from the University of Tsukuba, and Teri Milner and Francis Lee from Weill Cornell Medical College. Along the way, the members of my faculty advisory committee gave me advice, which was sometimes difficult for me to take but invariably strengthened my project. Thanks to Peter Schmidt from the NIH for making the journey to NYC for my thesis defense. The graduate school at Rockefeller and the MD-PhD program office ensured that my time in graduate school was spent worrying about scientific problems, not financial or administrative ones. And finally, my advisor, Bruce, instilled in me several principles that I will carry with me for my entire scientific career. His emphasis on “top-down” investigation taught me to never lose sight of the relevance of my work to overall brain function and behavior. In his willingness to interact with the government, the press, and the scientific community, all of whom frequently v seek his expertise, he exemplifies a true scientist who reaches beyond experiments and publications to communicate with the public. Being his student opened every opportunity for conversation and collaboration with other scientists. In these endeavors I experienced first-hand the power of communication between investigators, which many labs shun out of fear of competition. Thank you, Bruce, not only for your inspiration by example, but for your daily input on my project and, when I needed it, your timely emotional support. I am proud to be a member of the ever-growing McEwen family. vi Table of Contents Page 1 Chapter 1: Introduction 1 Estradiol enhances hippocampal function in rodents and humans 4 Estradiol enhances hippocampal synaptic plasticity 10 Estradiol acts on estrogen receptors via nuclear- and membrane- initiated signaling 15 Mechanism of estradiol enhancement of hippocampal synaptic plasticity 20 Rodent Models 22 Study Design 24 Chapter 2: A murine model to study estradiol effects in the hippocampus 25 Female C57BL/6J mice have regular cycles with predictable hormone levels and uterine weights 28 The mouse hippocampal formation contains extranuclear ERs 35 Discussion 38 Chapter 3: Rapid and physiological effects of estradiol on Akt 39 Akt activation fluctuates across the estrous cycle 42 Estradiol rapidly activates Akt and increases PSD-95 expression 45 Rapid estradiol effects on Akt require estrogen receptors 46 Discussion 50 Chapter 4: Physiological effect of estradiol on TrkB activation 51 TrkB activation fluctuates across the estrous cycle 53 Hippocampal TrkB mRNA does not fluctuate across the estrous cycle 55 Estradiol increases BDNF expression and TrkB activation 61 Estradiol induction of BDNF requires estrogen receptor beta 63 Discussion 66 Chapter 5: Ultrastructural distribution of pTrkB depends on sex and cycle stage 68 Light micoscopic immunolocalization of pTrkB 70 Presynaptic profiles contain the most abundant pTrkB-ir 72 Axons and axon terminals, including mossy fibers, contain pTrkB-ir 80 Dendrites and dendritic spines contain pTrkB-ir vii 84 Glial profiles contain pTrkB-ir 85 Few synaptic profiles contain pTrkB-ir 86 pTrkB in axons increases in proestrus 90 Discussion 91 Methodological considerations 92 pTrkB is positioned to locally regulate synaptic transmission and neurite growth 94 pTrkB is positioned to regulate glial cell function 94 Presynaptic pTrkB is implicated in estrous cycle fluctuation of BDNF signaling 98 Sex differences in the distribution of pTrkB may reflects the influence of estradiol 98 Summary 100 Chapter 6: BDNF variant Val66Met modifies the estrous cycling of hippocampal function 102 Met/Met mice are reproductively normal 104 Met/Met mice show differences in non-mnemonic behaviors 108 Met/Met mice exhibit memory impairment 112 Estrous cycle affects the Val66Met cognitive phenotype 114 Met/Met hippocampi show increased BDNF and TrkB expression 117 Val66Met alters estrous cycle fluctuation of Akt and PSD-95 123 Discussion 123 Behavioral and molecular effects of BDNF variant Val66Met 125 Estradiol effects in wild type (Val/Val) mice 129 Estradiol effects in BDNF variant Val66Met mice 132 Implications for human behavior 134 Chapter 7: Discussion 135 Mechanism of estradiol effects on hippocampal function 137 Physiology vs. pharmacology
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