Intriguing Roles of Hippocampus-Synthesized 17β-Estradiol in the Modulation of Hippocampal Synaptic Plasticity

Journal of Molecular Neuroscience

Volumn 54, Issue 2, 2014, Pages 271-281

  Bian, Chen ^a   Zhu, Haitao ^a   Zhao, Yangang ^a   Cai, Wenqin ^a   Zhang, Jiqiang ^a  

^a THIRD MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

17 Estradiol; Aromatase; De novo synthesis; Hippocampus; Steroid receptor coactivator 1; Synaptic plasticity

Indexed keywords

ESTRADIOL; ESTROGEN RECEPTOR;

ANIMAL; BIOSYNTHESIS; GENETICS; HIPPOCAMPUS; HUMAN; METABOLISM; NERVE CELL PLASTICITY; PHYSIOLOGY;

ANIMALS; ESTRADIOL; HIPPOCAMPUS; HUMANS; NEURONAL PLASTICITY; RECEPTORS, ESTROGEN;

EID: 84929940577     PISSN: 08958696     EISSN: 15591166     Source Type: Journal    
DOI: 10.1007/s12031-014-0285-8     Document Type: Article

References (102)

1. Akama KT, Thompson LI, Milner TA, McEwen BS (2013) 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. J Biol Chem 288:6438–6450
2. Alejandre-Gomez M, Garcia-Segura LM, Gonzalez-Burgos I (2007) Administration of an inhibitor of estrogen biosynthesis facilitates working memory acquisition in male rats. Neurosci Res 58:272–277
3. Anthoni H, Sucheston LE, Lewis BA, Tapia-Paez I, Fan X, Zucchelli M, Taipale M, Stein CM, Hokkanen ME, Castren E, Pennington BF, Smith SD, Olson RK, Tomblin JB, Schulte-Korne G, Nothen M, Schumacher J, Muller-Myhsok B, Hoffmann P, Gilger JW, Hynd GW, Nopola-Hemmi J, Leppanen PH, Lyytinen H, Schoumans J, Nordenskjold M, Spencer J, Stanic D, Boon WC, Simpson E, Makela S, Gustafsson JA, Peyrard-Janvid M, Iyengar S, Kere J (2012) The aromatase gene CYP19A1: several genetic and functional lines of evidence supporting a role in reading, speech and language. Behav Genet 42:509–527
4. Balthazart J, Baillien M, Ball GF (2006) Rapid control of brain aromatase activity by glutamatergic inputs. Endocrinology 147:359–366
5. Bender CM, Sereika SM, Brufsky AM, Ryan CM, Vogel VG, Rastogi P, Cohen SM, Casillo FE, Berga SL (2007) Memory impairments with adjuvant anastrozole versus tamoxifen in women with early-stage breast cancer. Menopause 14:995–998
6. Bi R, Broutman G, Foy MR, Thompson RF, Baudry M (2000) The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc Natl Acad Sci U S A 97:3602–3607
7. Bian C, Zhang D, Guo Q, Cai W, Zhang J (2011) Localization and sex-difference of steroid receptor coactivator-1 immunoreactivities in the brain of adult female and male mice. Steroids 76:269–279
8. Bian C, Zhu K, Guo Q, Xiong Y, Cai W, Zhang J (2012a) Sex differences and synchronous development of steroid receptor coactivator-1 and synaptic proteins in the hippocampus of postnatal female and male C57BL/6 mice. Steroids 77:149–156
9. Bian C, Zhu K, Yang L, Lin S, Li S, Su B, Zhang J (2012b) Gonadectomy differentially regulates steroid receptor coactivator-1 and synaptic proteins in the hippocampus of adult female and male C57BL/6 mice. Synapse 66:849–857
10. Chamniansawat S, Chongthammakun S (2012) A priming role of local estrogen on exogenous estrogen-mediated synaptic plasticity and neuroprotection. Exp Mol Med 44:403–411
11. Charlier TD (2009) Importance of steroid receptor coactivators in the modulation of steroid action on brain and behavior. Psychoneuroendocrinology 34(Suppl 1):S20–S29
12. Collins B, Mackenzie J, Stewart A, Bielajew C, Verma S (2009) Cognitive effects of hormonal therapy in early stage breast cancer patients: a prospective study. Psychooncology 18:811–821
13. Craig MC, Maki PM, Murphy DG (2005) The Women’s Health Initiative Memory Study: findings and implications for treatment. Lancet Neurol 4:190–194
14. Cyr M, Ghribi O, Thibault C, Morissette M, Landry M, Di Paolo T (2001) Ovarian steroids and selective estrogen receptor modulators activity on rat brain NMDA and AMPA receptors. Brain Res Brain Res Rev 37:153–161
15. Daniel S, Diaz AJ, Martinez KM, Bench BJ, Albertorio F, Cremer PS (2007) Separation of membrane-bound compounds by solid-supported bilayer electrophoresis. J Am Chem Soc 129:8072–8073
16. Fester L, Zhou L, Butow A, Huber C, von Lossow R, Prange-Kiel J, Jarry H, Rune GM (2009) Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus. Hippocampus 19:692–705
17. Fester L, Prange-Kiel J, Jarry H, Rune GM (2011) Estrogen synthesis in the hippocampus. Cell Tissue Res 345:285–294
18. Fester L, Prange-Kiel J, Zhou L, Blittersdorf BV, Bohm J, Jarry H, Schumacher M, Rune GM (2012) Estrogen-regulated synaptogenesis in the hippocampus: sexual dimorphism in vivo but not in vitro. J Steroid Biochem Mol Biol 131:24–29
19. Foster TC (2012) Role of estrogen receptor alpha and beta expression and signaling on cognitive function during aging. Hippocampus 22:656–669
20. Funakoshi T, Yanai A, Shinoda K, Kawano MM, Mizukami Y (2006) G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane. Biochem Biophys Res Commun 346:904–910
21. Furukawa A, Miyatake A, Ohnishi T, Ichikawa Y (1998) Steroidogenic acute regulatory protein (StAR) transcripts constitutively expressed in the adult rat central nervous system: colocalization of StAR, cytochrome P-450SCC (CYP XIA1), and 3beta-hydroxysteroid dehydrogenase in the rat brain. J Neurochem 71:2231–2238
22. Grassi S, Frondaroli A, Dieni C, Scarduzio M, Pettorossi VE (2009) Long-term potentiation in the rat medial vestibular nuclei depends on locally synthesized 17beta-estradiol. J Neurosci 29:10779–10783
23. Grassi S, Tozzi A, Costa C, Tantucci M, Colcelli E, Scarduzio M, Calabresi P, Pettorossi VE (2011) Neural 17beta-estradiol facilitates long-term potentiation in the hippocampal CA1 region. Neuroscience 192:67–73
24. Gu Q, Moss RL (1998) Novel mechanism for non-genomic action of 17 beta-oestradiol on kainate-induced currents in isolated rat CA1 hippocampal neurones. J Physiol 506(Pt 3):745–754
25. Hajszan T, Milner TA, Leranth C (2007) Sex steroids and the dentate gyrus. Prog Brain Res 163:399–415
26. Hammond R, Gibbs RB (2011) GPR30 is positioned to mediate estrogen effects on basal forebrain cholinergic neurons and cognitive performance. Brain Res 1379:53–60
27. Hammond R, Nelson D, Kline E, Gibbs RB (2012) Chronic treatment with a GPR30 antagonist impairs acquisition of a spatial learning task in young female rats. Horm Behav 62:367–374
28. Hero M, Maury S, Luotoniemi E, Service E, Dunkel L (2010) Cognitive effects of aromatase inhibitor therapy in peripubertal boys. Eur J Endocrinol 163:149–155
29. Hilton GD, Nunez JL, McCarthy MM (2003) Sex differences in response to kainic acid and estradiol in the hippocampus of newborn rats. Neuroscience 116:383–391
30. Hojo Y, Hattori TA, Enami T, Furukawa A, Suzuki K, Ishii HT, Mukai H, Morrison JH, Janssen WG, Kominami S, Harada N, Kimoto T, Kawato S (2004) Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons. Proc Natl Acad Sci U S A 101:865–870
31. Hojo Y, Higo S, Ishii H, Ooishi Y, Mukai H, Murakami G, Kominami T, Kimoto T, Honma S, Poirier D, Kawato S (2009) Comparison between hippocampus-synthesized and circulation-derived sex steroids in the hippocampus. Endocrinology 150:5106–5112
32. Hojo Y, Higo S, Kawato S, Hatanaka Y, Ooishi Y, Murakami G, Ishii H, Komatsuzaki Y, Ogiue-Ikeda M, Mukai H, Kimoto T (2011) Hippocampal synthesis of sex steroids and corticosteroids: essential for modulation of synaptic plasticity. Front Endocrinol (Lausanne) 2:43
33. Ishii H, Tsurugizawa T, Ogiue-Ikeda M, Asashima M, Mukai H, Murakami G, Hojo Y, Kimoto T, Kawato S (2007) Local production of sex hormones and their modulation of hippocampal synaptic plasticity. Neuroscientist 13:323–334
34. Johnson AB, O’Malley BW (2012) Steroid receptor coactivators 1, 2, and 3: critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy. Mol Cell Endocrinol 348:430–439
35. Kawato S, Hojo Y, Kimoto T (2002) Histological and metabolism analysis of P450 expression in the brain. Methods Enzymol 357:241–249
36. Kelly MJ, Ronnekleiv OK (2009) Control of CNS neuronal excitability by estrogens via membrane-initiated signaling. Mol Cell Endocrinol 308:17–25
37. Kim HJ, Casadesus G (2010) Estrogen-mediated effects on cognition and synaptic plasticity: what do estrogen receptor knockout models tell us? Biochim Biophys Acta 1800:1090–1093
38. Kimoto T, Tsurugizawa T, Ohta Y, Makino J, Tamura H, Hojo Y, Takata N, Kawato S (2001) Neurosteroid synthesis by cytochrome p450-containing systems localized in the rat brain hippocampal neurons: N-methyl-d-aspartate and calcium-dependent synthesis. Endocrinology 142:3578–3589
39. Konkle AT, McCarthy MM (2011) Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain. Endocrinology 152:223–235
40. Kretz O, Fester L, Wehrenberg U, Zhou L, Brauckmann S, Zhao S, Prange-Kiel J, Naumann T, Jarry H, Frotscher M, Rune GM (2004) Hippocampal synapses depend on hippocampal estrogen synthesis. J Neurosci 24:5913–5921
41. Leranth C, Petnehazy O, MacLusky NJ (2003) Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci 23:1588–1592
42. Logan SM, Sarkar SN, Zhang Z, Simpkins JW (2011) Estrogen-induced signaling attenuates soluble Abeta peptide-mediated dysfunction of pathways in synaptic plasticity. Brain Res 1383:1–12
43. Maki PM, Henderson VW (2012) Hormone therapy, dementia, and cognition: the Women’s Health Initiative 10 years on. Climacteric 15:256–262
44. McCullough LD, Blizzard K, Simpson ER, Oz OK, Hurn PD (2003) Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection. J Neurosci 23:8701–8705
45. Meng FT, Ni RJ, Zhang Z, Zhao J, Liu YJ, Zhou JN (2011) Inhibition of oestrogen biosynthesis induces mild anxiety in C57BL/6J ovariectomized female mice. Neurosci Bull 27:241–250
46. Molenda-Figueira HA, Williams CA, Griffin AL, Rutledge EM, Blaustein JD, Tetel MJ (2006) Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats. Horm Behav 50:383–392
47. Mukai H, Takata N, Ishii HT, Tanabe N, Hojo Y, Furukawa A, Kimoto T, Kawato S (2006a) Hippocampal synthesis of estrogens and androgens which are paracrine modulators of synaptic plasticity: synaptocrinology. Neuroscience 138:757–764
48. Mukai H, Tsurugizawa T, Ogiue-Ikeda M, Murakami G, Hojo Y, Ishii H, Kimoto T, Kawato S (2006b) Local neurosteroid production in the hippocampus: influence on synaptic plasticity of memory. Neuroendocrinology 84:255–263
49. Mukai H, Kimoto T, Hojo Y, Kawato S, Murakami G, Higo S, Hatanaka Y, Ogiue-Ikeda M (2010) Modulation of synaptic plasticity by brain estrogen in the hippocampus. Biochim Biophys Acta 1800:1030–1044
50. Munetsuna E, Hattori M, Komatsu S, Sakimoto Y, Ishida A, Sakata S, Hojo Y, Kawato S, Yamazaki T (2009a) Social isolation stimulates hippocampal estradiol synthesis. Biochem Biophys Res Commun 379:480–484
51. Munetsuna E, Hojo Y, Hattori M, Ishii H, Kawato S, Ishida A, Kominami SA, Yamazaki T (2009b) Retinoic acid stimulates 17beta-estradiol and testosterone synthesis in rat hippocampal slice cultures. Endocrinology 150:4260–4269
52. Murakami G, Tsurugizawa T, Hatanaka Y, Komatsuzaki Y, Tanabe N, Mukai H, Hojo Y, Kominami S, Yamazaki T, Kimoto T, Kawato S (2006) Comparison between basal and apical dendritic spines in estrogen-induced rapid spinogenesis of CA1 principal neurons in the adult hippocampus. Biochem Biophys Res Commun 351:553–558
53. Niessen NA, Balthazart J, Ball GF, Charlier TD (2011) Steroid receptor coactivator 2 modulates steroid-dependent male sexual behavior and neuroplasticity in Japanese quail (Coturnix japonica). J Neurochem 119:579–593
54. Nishihara E, Yoshida-Komiya H, Chan CS, Liao L, Davis RL, O’Malley BW, Xu J (2003) SRC-1 null mice exhibit moderate motor dysfunction and delayed development of cerebellar Purkinje cells. J Neurosci 23:213–222
55. Ogawa H, Nishi M, Kawata M (2001) Localization of nuclear coactivators p300 and steroid receptor coactivator 1 in the rat hippocampus. Brain Res 890:197–202
56. Parducz A, Hajszan T, Maclusky NJ, Hoyk Z, Csakvari E, Kurunczi A, Prange-Kiel J, Leranth C (2006) Synaptic remodeling induced by gonadal hormones: neuronal plasticity as a mediator of neuroendocrine and behavioral responses to steroids. Neuroscience 138:977–985
57. Pierman S, Sica M, Allieri F, Viglietti-Panzica C, Panzica GC, Bakker J (2008) Activational effects of estradiol and dihydrotestosterone on social recognition and the arginine–vasopressin immunoreactive system in male mice lacking a functional aromatase gene. Horm Behav 54:98–106
58. Pisani SL, Neese SL, Doerge DR, Helferich WG, Schantz SL, Korol DL (2012) Acute genistein treatment mimics the effects of estradiol by enhancing place learning and impairing response learning in young adult female rats. Horm Behav 62:491–499
59. Prange-Kiel J, Rune GM (2006) Direct and indirect effects of estrogen on rat hippocampus. Neuroscience 138:765–772
60. Prange-Kiel J, Wehrenberg U, Jarry H, Rune GM (2003) Para/autocrine regulation of estrogen receptors in hippocampal neurons. Hippocampus 13:226–234
61. Prange-Kiel J, Jarry H, Schoen M, Kohlmann P, Lohse C, Zhou L, Rune GM (2008) Gonadotropin-releasing hormone regulates spine density via its regulatory role in hippocampal estrogen synthesis. J Cell Biol 180:417–426
62. Qin L, Chen X, Wu Y, Feng Z, He T, Wang L, Liao L, Xu J (2011) Steroid receptor coactivator-1 upregulates integrin alpha(5) expression to promote breast cancer cell adhesion and migration. Cancer Res 71:1742–1751
63. Register TC, Shively CA, Lewis CE (1998) Expression of estrogen receptor alpha and beta transcripts in female monkey hippocampus and hypothalamus. Brain Res 788:320–322
64. Rosati F, Sturli N, Cungi MC, Morello M, Villanelli F, Bartolucci G, Finocchi C, Peri A, Serio M, Danza G (2011) Gonadotropin-releasing hormone modulates cholesterol synthesis and steroidogenesis in SH-SY5Y cells. J Steroid Biochem Mol Biol 124:77–83
65. Rune GM, Frotscher M (2005) Neurosteroid synthesis in the hippocampus: role in synaptic plasticity. Neuroscience 136:833–842
66. Rune GM, Lohse C, Prange-Kiel J, Fester L, Frotscher M (2006) Synaptic plasticity in the hippocampus: effects of estrogen from the gonads or hippocampus? Neurochem Res 31:145–155
67. Schulz K, Korz V (2010) Hippocampal testosterone relates to reference memory performance and synaptic plasticity in male rats. Front Behav Neurosci 4:187
68. Schwarz JM, Liang SL, Thompson SM, McCarthy MM (2008) Estradiol induces hypothalamic dendritic spines by enhancing glutamate release: a mechanism for organizational sex differences. Neuron 58:584–598
69. Segal M, Murphy DD (1998) CREB activation mediates plasticity in cultured hippocampal neurons. Neural Plast 6:1–7
70. Shang XL, Zhao JH, Cao YP, Xue YX (2010) Effects of synaptic plasticity regulated by 17beta-estradiol on learning and memory in rats with Alzheimer’s disease. Neurosci Bull 26:133–139
71. Sharma K, Mehra RD (2008) Long-term administration of estrogen or tamoxifen to ovariectomized rats affords neuroprotection to hippocampal neurons by modulating the expression of Bcl-2 and Bax. Brain Res 1204:1–15
72. Sherwin BB (2002) Estrogen and cognitive functioning in men with mild cognitive impairment. J Mol Neurosci 19:219–223
73. Sherwin BB (2005) Surgical menopause, estrogen, and cognitive function in women: what do the findings tell us? Ann N Y Acad Sci 1052:3–10
74. Shibuya K, Takata N, Hojo Y, Furukawa A, Yasumatsu N, Kimoto T, Enami T, Suzuki K, Tanabe N, Ishii H, Mukai H, Takahashi T, Hattori TA, Kawato S (2003) Hippocampal cytochrome P450s synthesize brain neurosteroids which are paracrine neuromodulators of synaptic signal transduction. Biochim Biophys Acta 1619:301–316
75. Shilling V, Jenkins V, Morris R, Deutsch G, Bloomfield D (2005) The effects of adjuvant chemotherapy on cognition in women with breast cancer—preliminary results of an observational longitudinal study. Breast 14:142–150
76. Sierra A, Lavaque E, Perez-Martin M, Azcoitia I, Hales DB, Garcia-Segura LM (2003) Steroidogenic acute regulatory protein in the rat brain: cellular distribution, developmental regulation and overexpression after injury. Eur J Neurosci 18:1458–1467
77. Smith JD, Chakrabarti E, Levin-Allerhand JA (2004) Drug discovery: estrogen-related compounds in mouse models of Alzheimer’s disease. J Mol Neurosci 24:145–147
78. Smith CC, Vedder LC, McMahon LL (2009) Estradiol and the relationship between dendritic spines, NR2B containing NMDA receptors, and the magnitude of long-term potentiation at hippocampal CA3–CA1 synapses. Psychoneuroendocrinology 34(Suppl 1):S130–S142
79. Spencer JL, Waters EM, Romeo RD, Wood GE, Milner TA, McEwen BS (2008) Uncovering the mechanisms of estrogen effects on hippocampal function. Front Neuroendocrinol 29:219–237
80. Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14:311–317
81. Tetel MJ, Acharya KD (2013) Nuclear receptor coactivators: regulators of steroid action in brain and behavior. J Neuroendocrinol 25:1209–1218
82. Toran-Allerand CD (2005) Estrogen and the brain: beyond ER-alpha, ER-beta, and 17beta-estradiol. Ann N Y Acad Sci 1052:136–144
83. Vasudevan N, Pfaff DW (2008) Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 29:238–257
84. Velazquez-Zamora DA, Garcia-Segura LM, Gonzalez-Burgos I (2012) Effects of selective estrogen receptor modulators on allocentric working memory performance and on dendritic spines in medial prefrontal cortex pyramidal neurons of ovariectomized rats. Horm Behav 61:512–517
85. Vierk R, Glassmeier G, Zhou L, Brandt N, Fester L, Dudzinski D, Wilkars W, Bender RA, Lewerenz M, Gloger S, Graser L, Schwarz J, Rune GM (2012) Aromatase inhibition abolishes LTP generation in female but not in male mice. J Neurosci 32:8116–8126
86. von Schassen C, Fester L, Prange-Kiel J, Lohse C, Huber C, Bottner M, Rune GM (2006) Oestrogen synthesis in the hippocampus: role in axon outgrowth. J Neuroendocrinol 18:847–856
87. Vouimba RM, Foy MR, Foy JG, Thompson RF (2000) 17beta-estradiol suppresses expression of long-term depression in aged rats. Brain Res Bull 53:783–787
88. Wehrenberg U, Prange-Kiel J, Rune GM (2001) Steroidogenic factor-1 expression in marmoset and rat hippocampus: co-localization with StAR and aromatase. J Neurochem 76:1879–1886
89. Weiland NG, Orikasa C, Hayashi S, McEwen BS (1997) Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats. J Comp Neurol 388:603–612
90. Woolley CS, McEwen BS (1992) Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci 12:2549–2554
91. Xu J, Li Q (2003) Review of the in vivo functions of the p160 steroid receptor coactivator family. Mol Endocrinol 17:1681–1692
92. Xu X, Zhang Z (2006) Effects of estradiol benzoate on learning-memory behavior and synaptic structure in ovariectomized mice. Life Sci 79:1553–1560
93. Xu J, Wu RC, O’Malley BW (2009) Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat Rev Cancer 9:615–630
94. Yamazaki T, Yamamoto M, Ishihara Y, Komatsu S, Munetsuna E, Onizaki M, Ishida A, Kawato S, Mukuda T (2013) De novo synthesized estradiol protects against methylmercury-induced neurotoxicity in cultured rat hippocampal slices. PLoS One 8:e55559
95. Yildirim M, Janssen WG, Lou WY, Akama KT, McEwen BS, Milner TA, Morrison JH (2011) Effects of estrogen and aging on the synaptic distribution of phosphorylated Akt-immunoreactivity in the CA1 region of the female rat hippocampus. Brain Res 1379:98–108
96. Yoder KM, Lu K, Vicario DS (2012) Blocking estradiol synthesis affects memory for songs in auditory forebrain of male zebra finches. Neuroreport 23:922–926
97. Yuste R, Bonhoeffer T (2001) Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 24:1071–1089
98. Zhang JQ, Cai WQ, Zhou DS, Su BY (2002) Distribution and differences of estrogen receptor beta immunoreactivity in the brain of adult male and female rats. Brain Res 935:73–80
99. Zhang S, Huang Y, Zhu YC, Yao T (2005) Estrogen stimulates release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase C pathway. Acta Pharmacol Sin 26:171–176
100. Zhang D, Guo Q, Bian C, Zhang J, Cai W, Su B (2011a) Expression of steroid receptor coactivator-1 was regulated by postnatal development but not ovariectomy in the hippocampus of rats. Dev Neurosci 33:57–63
101. Zhang D, Guo Q, Bian C, Zhang J, Lin S, Su B (2011b) Alterations of steroid receptor coactivator-1 (SRC-1) immunoreactivities in specific brain regions of young and middle-aged female Sprague–Dawley rats. Brain Res 1382:88–97
102. Zhou L, Fester L, von Blittersdorff B, Hassu B, Nogens H, Prange-Kiel J, Jarry H, Wegscheider K, Rune GM (2010) Aromatase inhibitors induce spine synapse loss in the hippocampus of ovariectomized mice. Endocrinology 151:1153–1160