Diverse Synaptic Distributions of G Protein‐coupled Estrogen Receptor 1 in Monkey Prefrontal Cortex with Aging and Menopause

Abstract Age‐ and menopause‐related impairment in working memory mediated by the dorsolateral prefrontal cortex (dlPFC) occurs in humans and nonhuman primates. Long‐term cyclic 17&bgr;‐estradiol treatment rescues cognitive deficits in aged ovariectomized rhesus monkeys while restoring highly plastic synapses. Here we tested whether distributions of G protein‐coupled estrogen receptor 1 (GPER1) within monkey layer III dlPFC synapses are sensitive to age and estradiol, and coupled to cognitive function. Ovariectomized young and aged monkeys administered vehicle or estradiol were first tested on a delayed response test of working memory. Then, quantitative serial section immunoelectron microscopy was used to determine the distributions of synaptic GPER1. GPER1‐containing nonperforated axospinous synapse density was reduced with age, and partially restored with estrogen treatment. The majority of synapses expressed GPER1, which was predominately localized to presynaptic cytoplasm and mitochondria. GPER1 was also abundant at plasmalemmas, and within cytoplasmic and postsynaptic density (PSD) domains of dendritic spines. GPER1 levels did not differ with age or treatment, and none of the variables examined were tightly associated with cognitive function. However, greater representation of GPER1 subjacent to the PSD accompanied higher synapse density. These data suggest that GPER1 is positioned to support diverse functions key to synaptic plasticity in monkey dlPFC.

[1]  E. Filardo,et al.  The G-protein coupled estrogen receptor, GPER: The inside and inside-out story , 2015, Molecular and Cellular Endocrinology.

[2]  A. Phan,et al.  Rapid effects of the G-protein coupled oestrogen receptor (GPER) on learning and dorsal hippocampus dendritic spines in female mice , 2015, Physiology & Behavior.

[3]  J. Mong,et al.  Neurocognitive effects of estrogens across the adult lifespan in nonhuman primates: State of knowledge and new perspectives , 2015, Hormones and Behavior.

[4]  J. Morrison,et al.  Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse. , 2015, Physiological reviews.

[5]  N. Zhang,et al.  Activation of GPR30 attenuates chronic pain-related anxiety in ovariectomized mice , 2015, Psychoneuroendocrinology.

[6]  B. McEwen,et al.  G-Protein-Coupled Estrogen Receptor 1 Is Anatomically Positioned to Modulate Synaptic Plasticity in the Mouse Hippocampus , 2015, The Journal of Neuroscience.

[7]  D. Srivastava,et al.  Molecular signature of rapid estrogen regulation of synaptic connectivity and cognition , 2015, Frontiers in Neuroendocrinology.

[8]  T. Milner,et al.  Medial prefrontal cortical estradiol rapidly alters memory system bias in female rats: ultrastructural analysis reveals membrane-associated estrogen receptors as potential mediators. , 2014, Endocrinology.

[9]  J. Morrison,et al.  G-protein coupled estrogen receptor, estrogen receptor α, and progesterone receptor immunohistochemistry in the hypothalamus of aging female rhesus macaques given long-term estradiol treatment. , 2014, Journal of experimental zoology. Part A, Ecological genetics and physiology.

[10]  S. Aquila,et al.  Identification of G protein‐coupled estrogen receptor in human and pig spermatozoa , 2014, Journal of anatomy.

[11]  G. Dohanich,et al.  Activation of G-protein-coupled receptor 30 is sufficient to enhance spatial recognition memory in ovariectomized rats , 2014, Behavioural Brain Research.

[12]  P. Evans,et al.  G‐Protein Oestrogen Receptor 1: Trials and Tribulations of a Membrane Oestrogen Receptor , 2013, Journal of neuroendocrinology.

[13]  D. Srivastava,et al.  Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens , 2013, Pharmacological Reviews.

[14]  Shui-bing Liu,et al.  Neuroprotective effect of estrogen: Role of nonsynaptic NR2B-containing NMDA receptors , 2013, Brain Research Bulletin.

[15]  Frank J. Yuk,et al.  Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses , 2013, Neurobiology of Aging.

[16]  B. McEwen,et al.  Post-synaptic Density-95 (PSD-95) Binding Capacity of G-protein-coupled Receptor 30 (GPR30), an Estrogen Receptor That Can Be Identified in Hippocampal Dendritic Spines* , 2013, The Journal of Biological Chemistry.

[17]  A. Arnsten,et al.  Neuromodulation of Thought: Flexibilities and Vulnerabilities in Prefrontal Cortical Network Synapses , 2012, Neuron.

[18]  J. Morrison,et al.  Neuronal and morphological bases of cognitive decline in aged rhesus monkeys , 2012, AGE.

[19]  R. Traystman,et al.  GPER1/GPR30 Activation Improves Neuronal Survival Following Global Cerebral Ischemia Induced by Cardiac Arrest in Mice , 2012, Translational Stroke Research.

[20]  R. Gibbs,et al.  Chronic treatment with a GPR30 antagonist impairs acquisition of a spatial learning task in young female rats , 2012, Hormones and Behavior.

[21]  Frank J. Yuk,et al.  Synaptic Distributions of GluA2 and PKMζ in the Monkey Dentate Gyrus and Their Relationships with Aging and Memory , 2012, The Journal of Neuroscience.

[22]  Weiqi Zhang,et al.  G-Protein-Coupled Receptor 30 Mediates Rapid Neuroprotective Effects of Estrogen via Depression of NR2B-Containing NMDA Receptors , 2012, The Journal of Neuroscience.

[23]  T. Simoncini,et al.  Actin Cytoskeleton Remodelling by Sex Steroids in Neurones , 2012, Journal of neuroendocrinology.

[24]  M. Maggiolini,et al.  Identification of the estrogen receptor GPER in neoplastic and non-neoplastic human testes , 2011, Reproductive biology and endocrinology : RB&E.

[25]  Daeyeol Lee,et al.  Neuronal basis of age-related working memory decline , 2011, Nature.

[26]  G. Botti,et al.  GPR30 is overexpressed in post-puberal testicular germ cell tumors , 2011, Cancer biology & therapy.

[27]  S. Andò,et al.  The G Protein-coupled Receptor 30 Is Up-regulated by Hypoxia-inducible Factor-1α (HIF-1α) in Breast Cancer Cells and Cardiomyocytes* , 2011, The Journal of Biological Chemistry.

[28]  J. Morrison,et al.  Synaptic Estrogen Receptor-α Levels in Prefrontal Cortex in Female Rhesus Monkeys and Their Correlation with Cognitive Performance , 2010, The Journal of Neuroscience.

[29]  M. Maggiolini,et al.  Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts. , 2010, Cancer research.

[30]  J. Morrison,et al.  Selective Changes in Thin Spine Density and Morphology in Monkey Prefrontal Cortex Correlate with Aging-Related Cognitive Impairment , 2010, The Journal of Neuroscience.

[31]  Mark H. Tuszynski,et al.  Age-related cognitive deficits in rhesus monkeys mirror human deficits on an automated test battery , 2010, Neurobiology of Aging.

[32]  C. Rosano,et al.  Estriol acts as a GPR30 antagonist in estrogen receptor-negative breast cancer cells , 2010, Molecular and Cellular Endocrinology.

[33]  Jun Noguchi,et al.  Structural dynamics of dendritic spines in memory and cognition , 2010, Trends in Neurosciences.

[34]  A. Musti,et al.  c-Jun activation is required for 4-hydroxytamoxifen-induced cell death in breast cancer cells , 2010, Oncogene.

[35]  R. Zukin,et al.  Acute Administration of Non-Classical Estrogen Receptor Agonists Attenuates Ischemia-Induced Hippocampal Neuron Loss in Middle-Aged Female Rats , 2010, PloS one.

[36]  B. Hille,et al.  Complete Reversible Refolding of a G-Protein Coupled Receptor on a Solid Support , 2016, PloS one.

[37]  S. Fuqua,et al.  G protein-coupled receptor 30 expression is up-regulated by EGF and TGF alpha in estrogen receptor alpha-positive cancer cells. , 2009, Molecular endocrinology.

[38]  R. Gibbs,et al.  Chronic treatment with estrogen receptor agonists restores acquisition of a spatial learning task in young ovariectomized rats , 2009, Hormones and Behavior.

[39]  V. Chevaleyre,et al.  Estradiol rescues neurons from global ischemia-induced cell death: Multiple cellular pathways of neuroprotection , 2009, Steroids.

[40]  E. Prossnitz,et al.  Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues , 2009, The Journal of endocrinology.

[41]  H. Fuchs,et al.  Expression pattern of G protein-coupled receptor 30 in LacZ reporter mice. , 2009, Endocrinology.

[42]  T. Prolla,et al.  Evolution of the Aging Brain Transcriptome and Synaptic Regulation , 2008, PloS one.

[43]  J. Herndon,et al.  Menopause in Nonhuman Primates?1 , 2008, Biology of reproduction.

[44]  J. Morrison,et al.  Aromatase distribution in the monkey temporal neocortex and hippocampus , 2008, Brain Research.

[45]  J. Morrison,et al.  Estrogen and aging affect synaptic distribution of phosphorylated LIM kinase (pLIMK) in CA1 region of female rat hippocampus , 2008, Neuroscience.

[46]  J. Morrison,et al.  Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex , 2007, Proceedings of the National Academy of Sciences.

[47]  J. Bourne,et al.  Do thin spines learn to be mushroom spines that remember? , 2007, Current Opinion in Neurobiology.

[48]  G. Shepherd,et al.  Transient and Persistent Dendritic Spines in the Neocortex In Vivo , 2005, Neuron.

[49]  Akihiko Takashima,et al.  Age-related changes of Alzheimer's disease-associated proteins in cynomolgus monkey brains. , 2003, Biochemical and biophysical research communications.

[50]  J. Morrison,et al.  Cyclic Estrogen Replacement Improves Cognitive Function in Aged Ovariectomized Rhesus Monkeys , 2003, The Journal of Neuroscience.

[51]  H. Kasai,et al.  Structure–stability–function relationships of dendritic spines , 2003, Trends in Neurosciences.

[52]  Ashley Acheson,et al.  Aging-related changes in release of growth hormone and luteinizing hormone in female rhesus monkeys. , 2002, The Journal of clinical endocrinology and metabolism.

[53]  S. Gill,et al.  Evidence that GnRH decreases with gonadal steroid feedback but increases with age in postmenopausal women. , 2002, The Journal of clinical endocrinology and metabolism.

[54]  J. Morrison,et al.  Estrogen and Aging Affect the Subcellular Distribution of Estrogen Receptor-α in the Hippocampus of Female Rats , 2002, The Journal of Neuroscience.

[55]  M. Sheng,et al.  Dentritic spines : structure, dynamics and regulation , 2001, Nature Reviews Neuroscience.

[56]  J. Morrison,et al.  Different modes of hippocampal plasticity in response to estrogen in young and aged female rats , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[57]  M. Voytko.  The effects of long-term ovariectomy and estrogen replacement therapy on learning and memory in monkeys (Macaca fascicularis). , 2000, Behavioral neuroscience.

[58]  J. Morrison,et al.  Differential synaptic localization of the glutamate transporter EAAC1 and glutamate receptor subunit gluR2 in the rat hippocampus , 2000, The Journal of comparative neurology.

[59]  D. Pandya,et al.  Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns , 1999, The European journal of neuroscience.

[60]  M. Fischer,et al.  Rapid Actin-Based Plasticity in Dendritic Spines , 1998, Neuron.

[61]  S. Pincus,et al.  Characteristics of luteinizing hormone secretion in younger versus older premenopausal women. , 1998, American journal of obstetrics and gynecology.

[62]  T. Kemper,et al.  Lack of correlation between plaque burden and cognition in the aged monkey , 1997, Acta Neuropathologica.

[63]  Lasley,et al.  Characterization of the onset of menopause in the rhesus macaque. , 1997, Biology of reproduction.

[64]  P. Rapp,et al.  Reproductive senescence predicts cognitive decline in aged female monkeys , 1997, Neuroreport.

[65]  Marla Gearing,et al.  Aβ 40 is a major form of β-amyloid in nonhuman primates , 1996, Neurobiology of Aging.

[66]  P. Goldman-Rakic.  Cellular basis of working memory , 1995, Neuron.

[67]  B. Lasley,et al.  Simple extraction and enzyme immunoassays for estrogen and progesterone metabolites in the feces of Macaca fascicularis during non-conceptive and conceptive ovarian cycles. , 1993, Biology of reproduction.

[68]  P. Goldman-Rakic,et al.  Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. , 1989, Journal of neurophysiology.

[69]  L. Squire,et al.  Human amnesia and animal models of amnesia: performance of amnesic patients on tests designed for the monkey. , 1988, Behavioral neuroscience.

[70]  H R Johnson,et al.  Aging in the rhesus monkey: debilitating effects on short-term memory. , 1978, Journal of gerontology.

[71]  J. Morrison,et al.  Synaptic health. , 2014, JAMA psychiatry.

[72]  J. Morrison,et al.  Estrogen Alters Spine Number and Morphology in Prefrontal Cortex of Aged Female Rhesus Monkeys , 2006, The Journal of Neuroscience.

[73]  B. Bavister,et al.  Ovarian senescence in the rhesus monkey (Macaca mulatta). , 2005, Human reproduction.

[74]  J. Tigges,et al.  A beta40 is a major form of beta-amyloid in nonhuman primates. , 1996, Neurobiology of aging.

[75]  S. B. Kater,et al.  Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. , 1994, Annual review of neuroscience.

[76]  J. Tigges,et al.  Survival rate and life span of rhesus monkeys at the Yerkes regional primate research center , 1988, American journal of primatology.