Estrogen Receptor Signaling in the Brain: A Trip Down Memory Lane

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Estrogen Receptor Signaling in the Brain: A Trip Down Memory Lane

Tuesday, May 25, 2010

The New York Academy of Sciences

Actions of estrogens are mediated via estrogen receptor ERa and ERß, both of which are widely expressed in the CNS. Estrogens have long been implicated in influencing memory processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERa) and beta (ERß) remain unclear. This symposium will start with an overview of estrogen and memory formation and the mechanisms of its actions, including effects on cell morphology, synapse formation, cellular signaling, and neuronal excitability. Physiologic and pharmacologic forms of estrogen affect cognitive behavior in mammals, which may be applicable to treatment of diseases with impaired cognition. To elucidate the mechanism underlying estrogens actions, the meeting will investigate how estrogen rapidly modifies the structure of synaptic spines and their underlying cytoskeleton. Acute infusions of ß-estradiol cause a rapid modest, and reversible increase in the size of field EPSPs and promote theta burst-induced long-term potentiation in hippocampal area CA1. These acute effects on synaptic responses and LTP involve signaling pathways leading to actin polymerization within dendritic spines. Complementing these studies, the effects of estrogen on hippocampal synaptic plasticity and memory, as mediated through ERß, will be examined. Selective ERß agonists increase key synaptic proteins and induce morphological changes in hippocampal neurons in vivo, enhance LTP and improve performance in hippocampus-dependent memory tasks. In addition, the differential impact of ERa and ERß activation on AMPA-receptor subunit GluR1 and associated proteins will be discussed. This data set suggests that targeting ERß may have therapeutic potential without the feminizing effects of estrogen. New insights will be presented from studies of young and aged female non-human primates on the interactive effects of aging and estrogen treatment on neuronal architecture and synaptic organization in hippocampus and prefrontal cortex. These data have important implications for the neurobiological basis of cognitive aging and also demonstrate the potential for protection against these age-related synaptic alterations and the related cognitive decline. This session will show the critical importance of estrogen signaling for memory formation and start to describe recent advances in dissecting out the pathways underlying these effects. This research should have a profound impact on how we consider estrogen-based therapies for diseases with memory deficits.

Agenda

*Presentation times are subject to change.


1:00 – 1:10 PM

Introduction
Feng Liu, PhD, Pfizer

1:15 – 1:55 PM

Cytoskeletal Changes Underlie Estrogen’s Acute Effects on Synaptic Transmission and Plasticity
Enikö Kramár, PhD, University of California, Irvine

2:00 – 2:40 PM

Activation of Estrogen Receptor Beta Regulates Hippocampal Synaptic Plasticity and Improves Memory
Feng Liu, PhD, Pfizer

2:45 – 3:15 PM

Coffee Break

3:15 – 4:00 PM

Estrogens and the Brain: Actions Above the Hypothalamuus via Novel Mechanisms
Bruce McEwen, PhD, Rockefeller University

4:00 – 4:45 PM

Interactive Effects of Age and Estrogen on Cortical Neurons: Implications for Cognitive Aging
John H. Morrison, PhD, Mount Sinai School of Medicine

4:45 – 5:00 PM

Closing Remarks
Feng Liu, PhD, Pfizer

Speakers

Organizer

Feng Liu, PhD

Pfizer

Feng Liu conducted her PhD thesis work at Fox Chase Cancer Center and received PhD in Biochemistry from Temple University in 1997. Then she continued her studies as a post-doctoral researcher in Dr. Paul Greengard's laboratory at the Rockefeller University. In Greengard's lab, Feng conducted research determining the impact of glutamate and dopamine in regulating synaptic activity through protein kinases. A highly productive effort resulted in novel inroads into synapse function, and publications of peer-reviewed articles. In 2002, Feng joined Neuroscience department at Wyeth Discovery Research in Princeton. She led the effort of identifying and validating a number of targets as well as extensive basic biology in Schizophrenia/Bipolar disorder areas. She also led a discovery breakthrough for ERβ biology that provided rationale and validation for pursing this target for multiple CNS therapeutics. Utilizing pharmacological, biochemical and behavioural techniques, she led a team of scientists to demonstrate for the first time that the effects of estrogens on hippocampal synaptic plasticity and memory in rodents are mediated through ERβ. Selective ERß agonists increase key synaptic proteins and induce morphological changes in hippocampal neurons in vivo, enhance LTP and improve performance in hippocampus-dependent memory tasks. This data set suggests that targeting ERß may have therapeutic potential without the feminizing effects of estrogens. Feng continues to lead the drug discovery effort at Pfizer of finding ERß selective agonist for treating CNS disorders, such as Alzheimer's disease and Schizophrenia. Dr. Liu holds two US patents and had published over 25 articles in journals such as Nature Neuroscience, PNAS, J. Biological Chemistry, Current Biology and JPET.

Speakers

Enikö Kramár, PhD

University of California, Irvine

Enikö A. Kramár graduated with a PhD in Neuroscience from Washington State University in 2000 and then continued her studies as a post-doctoral researcher in Dr. Gary Lynch’s laboratory at the UC Irvine (UCI). Supported by a NIH post-doctorate fellowship, Kramár made a series of discoveries showing that adhesion receptors belonging to the integrin family play a critical role in the consolidation (as opposed to induction and initial expression) of long-term potentiation (LTP). Using a method she helped invent, Kramár then found that integrins exert their consolidation effects by promoting the stabilization of actin networks that form shortly after LTP induction. Following promotion to an Assistant Researcher position in 2003, Kramár expanded her research program to include the question of whether integrins interact with releasable 'synaptic modifiers' to regulate the cytoskeletal changes underlying consolidation. This collaborative work ultimately resulted in the first clear descriptions of how Brain-Derived Neurotrophic Factor (BDNF) and adenosine modulate LTP consolidation. Before leaving to accept a position in industry in 2006, Dr. Kramár had published over 25 articles in journals such as PNAS, J. Biological Chemistry, and J. Neurosci. She returned to academia in 2007 as an Associate Project Scientist (UCI) to initiate a new research program testing if the plasticity and memory losses associated with low levels of estrogen can be explained within her model of LTP consolidation. These experiments led to the proposal that estrogen is itself a synaptic modifier acting positively on the same actin signaling pathways suppressed by adenosine. They have also pointed to a novel therapeutic strategy for offsetting the plasticity deficits that accompany conditions (e.g., menopause) in which estrogen levels are chronically depressed.

Bruce McEwen, PhD

Rockefeller University

Bruce S. McEwen, PhD, is the Alfred E. Mirsky Professor and Head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University. He is a member of the US National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences and a Fellow of the New York Academy of Sciences. He served as Dean of Graduate Studies from 1991-3 and as President of the Society for Neuroscience in 1997-98. As a neuroscientist and neuroendocrinologist, McEwen studies environmentally-regulated, variable gene expression in brain mediated by circulating steroid hormones and endogenous neurotransmitters in relation to brain sexual differentiation and the actions of sex, stress and thyroid hormones on the adult brain. His laboratory discovered adrenal steroid receptors in the hippocampus in 1968. His laboratory combines molecular, anatomical, pharmacological, physiological and behavioral methodologies and relates their findings to human clinical information. His current research focuses on stress effects on amygdala and prefrontal cortex as well as hippocampus, and his laboratory also investigates sex hormone effects and sex differences in these brain regions. In addition, he served on the MacArthur Foundation Research Network on Socioeconomic Status and Health, in which he helped to reformulate concepts and measurements related to stress and stress hormones in the context of human societies. This led to the concept of “allostatic load” that describes the wear and tear on the body and brain from chronic stress and related life style behaviors that lead to dysregulation of physiological stress pathways that are normally protective. He is also a member of the National Council on the Developing Child which focuses on healthy brain development as a key to physical and mental health. He is the co-author of book with science writer Elizabeth Lasley for a lay audience called “The End of Stress as We Know It” published in 2002 by the Joseph Henry Press and the Dana Press and another book with science writer Harold M. Schmeck, Jr. called “The Hostage Brain” published in 1994 by The Rockefeller University Press.

John H. Morrison

Mount Sinai School of Medicine

Dr. John H. Morrison is Dean of Basic Sciences and the Graduate School of Biological Sciences, Professor of Neuroscience, and the Willard T.C. Johnson Professor of Geriatrics and Adult Development in Neurobiology of Aging at the Mount Sinai School of Medicine. Prior to becoming Dean, Dr. Morrison served as Chair of the Department of Neuroscience.

Dr. Morrison earned his doctorate from Johns Hopkins University in 1979 and completed postdoctoral studies at the Salk Institute for Biological Studies. He then served as a faculty member at The Salk Institute and The Scripps Research Institute. In 1989, he joined the faculty at Mount Sinai.

Dr. Morrison’s research incorporates basic neurobiological research on neuronal specialization and the biochemical coding of brain circuits with human neuropathology in order to illuminate the cellular events that lead to Alzheimer’s disease. His research also focuses on the neurobiological events that accompany normal aging, as well as the differences between these events and those that accompany Alzheimer’s disease. Within this context, Dr. Morrison is interested in the effects of estrogen on the cerebral cortex, the interface between endocrine and neural aging, and the effects of stress on cortical neurons. Since 1985 the National Institutes of Health has funded Dr. Morrison’s research without interruption. He currently directs a large program on estrogen and the aging brain funded by the National Institute on Aging (NIA), as well as one on the neurobiological basis of cognitive aging that has been designated as an NIA MERIT Award. In addition Dr. Morrison is a project leader in the NIMH-funded Conte Center for the Neuroscience of Fear and Anxiety.

Dr. Morrison has published more than 250 scholarly works on the molecular, cellular, and neuroanatomic organization of the cerebral cortex, the cellular pathology of neurodegenerative disorders, and the neurobiology of aging. He is ranked among the most highly cited investigators in neuroscience (i.e. ISIHighlyCited/Neuroscience), and has served on multiple editorial boards.

Dr. Morrison is the recipient of numerous research awards and is a Fellow in both the New York Academy of Sciences (NYAS) and the American Association for the Advancement of Science (AAAS). He has served on advisory boards and review committees of several leading scientific organizations, including the National Institute of Aging, National Institute of Mental Health, The Howard Hughes Medical Institute, Society for Neuroscience, American Federation for Aging Research, and Amyotrophic Lateral Sclerosis Association.

Abstracts

Cytoskeletal Changes Underlie Estrogen’s Acute Effects on Synaptic Transmission and Plasticity

Enikö Kramár, PhD, University of California, Irvine

Estrogen is a rapid and extremely potent facilitator of plasticity in adult brain. Infusions of β-estradiol cause a rapid (<20 min), modest, and reversible increase in the size of synaptic responses and promote induction of long-term potentiation (LTP) in hippocampus. The mechanisms involved in these effects, though likely to be important to the cognitive effects of the steroid, are largely unknown. This presentation will first describe evidence that estrogen’s acute effects on synaptic responses and LTP involve signaling pathways leading to actin polymerization within dendritic spines. The relevance of the findings to conditions in which serum estrogen levels are chronically reduced will then be discussed. This will include a summary of results suggesting that acute applications of estrogen offset the plasticity deficits that follow chronic estrogen losses. Discussion of a general hypothesis regarding the role of the spine cytoskeleton in memory disturbances, including those associated with menopause, will conclude the presentation.

Activation of Estrogen Receptor Beta Regulates Hippocampal Synaptic Plasticity and Improves Memory

Feng Liu, PhD, Pfizer

Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the relative roles of the estrogen receptors alpha (ERα) and beta (ERβ) remain unclear. Utilizing pharmacological, biochemical and behavioral techniques, we demonstrate for the first time that the effects of estrogen on hippocampal synaptic plasticity and memory in rodents are mediated through ERβ. Selective ERβ agonists increased levels of key synaptic proteins in vivo including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERβ knockout mice. In hippocampal slices ERβ activation enhanced long-term potentiation (LTP), an effect that was absent in slices from ERβ knockout mice. ERβ activation induced morphological changes in hippocampal neurons in vivo including increased dendritic branching and density of mushroom-type spines. An ERβ agonist, but not an ERβ agonist, also improved performance in a variety of hippocampal-dependent memory tasks. Recent studies revealed that a new mechanism by which ERβ activation regulates synaptic plasticity, specifically through regulating protein translation. These findings elucidate an ERβ-mediated mechanism by which estrogen may influence synaptic plasticity in the hippocampus and ultimately learning and memory. Activation of this pathway may confer some of the CNS-mediated benefits of estrogen without the feminizing side effects, and offer a new therapeutic approach for diseases with cognitive deficits such as Alzheimer’s disease and schizophrenia.

Estrogens and the Brain: Actions Above the Hypothalamuus via Novel Mechanisms

Bruce McEwen, PhD, Rockefeller University

The adult brain is much more resilient and adaptable than previously believed, and adaptive structural plasticity involves growth and shrinkage of dendritic trees, turnover of synapses and limited amounts of neurogenesis in the forebrain, especially the dentate gyrus of the hippocampal formation. Stress and sex hormones help to mediate such plasticity, which has been extensively investigated in hippocampus and to a lesser extent in prefrontal cortex and amygdala, all brain regions that are involved in cognitive and emotional functions. Stress and sex hormones exert their effects on brain structural remodeling through both classical genomic and non-genomic mechanisms and they do so synergistically with neurotransmitters and other intra- and extracellular mediators. This will be illustrated for estrogen actions on synapse formation in the hippocampus via intracellular estrogen receptors located in dendrites, synapses, mitochondria and glial cell processes. A loss of this type of plasticity, ie, a loss of resilience, may be a key aspect of mood, anxiety and cognitive disorders and be particularly important in aging. Supported by NIH Grants NS07080, MH41256.

Interactive Effects of Age and Estrogen on Cortical Neurons: Implications for Cognitive Aging

John H. Morrison, PhD, Mount Sinai School of Medicine

Our studies of cyclical estradiol (E) treatment in ovariectomized (OVX) young and aged rhesus monkeys have revealed compelling cognitive and neurobiological effects of E in the context of aging. This presentation will focus primarily on area 46 of dorsolateral prefrontal cortex (dlPFC), a cortical area that mediates high-level cognitive processes, yet is highly vulnerable to aging. Young adult and aged OVX female rhesus monkeys are given either cyclical E or vehicle (V) for 2-3 years while undergoing cognitive testing, followed by extensive microscopic analyses of multiple cellular and synaptic indices. Delayed response (DR), a task that is particularly sensitive to tasks that require area 46 of the dlPFC was used as one of our key cognitive tests, which revealed the following: 1) young OVX rhesus monkeys performed equally well on DR performance with or without E, and 2) aged animals with E perform similar to young adults with or without E, whereas aged animals with V display significant impairment on DR. We have analyzed the structure of layer III pyramidal cells within dlPFC in these same monkeys. There are both age and treatment effects on these neurons that are consistent with the behavioral data. Briefly, reconstructions of pyramidal neurons in area 46 of these same monkeys showed that E increased the density of small, thin spines in both young and aged monkeys. However, this effect of E was against a background of age-related loss of small, thin spines, leaving aged V monkeys with a particularly low density of these highly plastic spines and vulnerable to cognitive decline. Thus, while ET partially restores a youthful phenotype to these neurons in aged monkeys, the aged untreated monkeys endure a “double hit” of age effects and lack of E that leaves them vulnerable. Importantly, the vulnerability of these neurons to age is partially reversible by ET which is reflected in the cognitive improvement seen in E treated aged female monkeys. Thus, E not only plays a critically important role in maintaining spine number, but also may enable synaptic plasticity through a cyclical increase in small highly plastic spines that may be consolidated in the context of learning.

We have now pursued the analysis of synaptic ER-α through postembedding immunogold electron microscopy in area 46 of these same monkeys. Not only is synaptic ER-α present in area 46 of dlPFC, but also the synaptic distribution and abundance of ER-α are not affected by age or treatment. This is likely due to the fact that ER-α is primarily localized in the large spine/synapses that are resistant to age-related loss. In addition, we found a correlation between abundance of synaptic ER-α and DR performance that may inform the cognitive resilience of young monkeys in the absence of circulating E. The implications of ER-α residing primarily in the large spines/synapses will be discussed in the context of potential dual mechanisms for enhancing cognitive performance.

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