title: Estrogen-mediated effects on cognition and synaptic plasticity: what do estrogen receptor knockout models tell us?
abstract: A plethora of evidence supports a beneficial role of estrogen in the brain. However, while these effects are hypothesized to be driven via the two main forms of estrogen receptors (ERα and ERß), the mechanism through which these receptors mediate estrogen's effects on cognition and plasticity remain unclear. Estrogen receptors are heterogeneously expressed in many cognition sensitive regions of the brain, have the ability to dimerize and heterodimerize, and are localized to both neurons and glia. In addition, while many of the known actions of estrogen through their receptor are mediated via the classical genomic regulatory mechanism of gene transcription, rapid non-genomic action of estrogens are also gaining relevance. These complex events make the mechanistic understanding of estrogen effects challenging. The development of transgenic estrogen receptor knockout mouse models has provided some much needed insight on the role of these receptors in mediating estrogen effects on cognition and synaptic plasticity. This review provides an overview of estrogen receptors in the brain and an update of knowledge gained from transgenic knockout models on cognition and synaptic plasticity.
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Gemma
authors.initials: G
authors.lastname: Casadesus
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D003071:Cognition / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D055503:Protein Multimerization / Q000502:physiology; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens
references.citation: J Neurosci. 2000 Jun 1;20(11):4248-54
references.pmid: 10818161
references.citation: Endocrinology. 1999 Mar;140(3):1044-7
references.pmid: 10067823
references.citation: Recent Prog Horm Res. 2002;57:357-84
references.pmid: 12017552
references.citation: Psychiatr Genet. 2006 Apr;16(2):85-8
references.pmid: 16538187
references.citation: J Comp Neurol. 2003 Oct 27;465(4):540-50
references.pmid: 12975814
references.citation: Mol Cell Biol. 2004 Sep;24(17):7681-94
references.pmid: 15314175
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5925-30
references.pmid: 8650195
references.citation: J Neurosci. 1997 Mar 1;17(5):1848-59
references.pmid: 9030643
references.citation: Psychoneuroendocrinology. 1988;13(4):345-57
references.pmid: 3067252
references.citation: Nat Neurosci. 2008 Mar;11(3):334-43
references.pmid: 18297067
references.citation: J Neuroendocrinol. 2009 Jul;21(7):640-7
references.pmid: 19453823
references.citation: Brain Res. 2000 Nov 17;883(2):258-64
references.pmid: 11074057
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5605-10
references.pmid: 20212170
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3996-4001
references.pmid: 11891272
references.citation: Exp Neurol. 2001 Feb;167(2):445-50
references.pmid: 11161633
references.citation: Front Neuroendocrinol. 2006 Jul;27(2):217-32
references.pmid: 16603234
references.citation: Endocr Rev. 1999 Jun;20(3):279-307
references.pmid: 10368772
references.citation: Endocrinology. 1997 Jan;138(1):507-10
references.pmid: 8977441
references.citation: Neuron. 1991 May;6(5):665-77
references.pmid: 1673848
references.citation: Endocrinology. 2003 May;144(5):2055-67
references.pmid: 12697714
references.citation: Eur J Neurosci. 2003 May;17(10):1997-2005
references.pmid: 12786965
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1476-81
references.pmid: 9037078
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13391-5
references.pmid: 11687663
references.citation: Endocr Rev. 1999 Jun;20(3):358-417
references.pmid: 10368776
references.citation: Horm Behav. 1997 Dec;32(3):176-83
references.pmid: 9454668
references.citation: J Neurosci. 2005 Sep 21;25(38):8776-87
references.pmid: 16177047
references.citation: J Neurochem. 2007 Feb;100(4):950-67
references.pmid: 17266735
references.citation: J Neurosci. 1990 Apr;10(4):1286-91
references.pmid: 2329377
references.citation: Hippocampus. 2006;16(5):453-63
references.pmid: 16526034
references.citation: Circ Res. 1998 Jul 27;83(2):224-9
references.pmid: 9686763
references.citation: Front Neuroendocrinol. 1998 Oct;19(4):253-86
references.pmid: 9799586
references.citation: J Neurosci. 2008 Aug 27;28(35):8660-7
references.pmid: 18753366
references.citation: Neurology. 1997 Jun;48(6):1517-21
references.pmid: 9191758
references.citation: Neurology. 2000 Feb 22;54(4):833-7
references.pmid: 10690972
references.citation: Brain Res Mol Brain Res. 1998 Feb;54(1):175-80
references.pmid: 9526077
references.citation: J Neurosci Res. 2003 Dec 1;74(5):637-43
references.pmid: 14635215
references.citation: Mol Ther. 2008 Sep;16(9):1587-93
references.pmid: 18594506
references.citation: Nature. 1988 Jan 7;331(6151):91-4
references.pmid: 3267207
references.citation: J Clin Endocrinol Metab. 1997 Dec;82(12):4258-65
references.pmid: 9398750
references.citation: Am J Physiol Endocrinol Metab. 2008 Sep;295(3):E637-47
references.pmid: 18577698
references.citation: Arch Neurol. 1994 Sep;51(9):896-900
references.pmid: 8080389
references.citation: J Comp Neurol. 1997 Dec 1;388(4):507-25
references.pmid: 9388012
references.citation: J Neurosci. 1990 Dec;10(12):4035-9
references.pmid: 2269895
references.citation: Clin Cancer Res. 2003 Jun;9(6):1980-9
references.pmid: 12796359
references.citation: Neurology. 2000 Jun 27;54(12):2212-7
references.pmid: 10881241
references.citation: Endocrinology. 1997 Mar;138(3):863-70
references.pmid: 9048584
references.citation: Brain Res Mol Brain Res. 1989 Dec;6(4):297-310
references.pmid: 2574404
references.citation: Glia. 1999 May;26(3):260-7
references.pmid: 10340766
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7093-100
references.pmid: 11416193
references.citation: J Comp Neurol. 1993 Oct 8;336(2):293-306
references.pmid: 8245220
references.citation: Horm Behav. 1998 Oct;34(2):140-8
references.pmid: 9799624
references.citation: Neuroscience. 2006 Sep 15;141(4):1793-800
references.pmid: 16797852
references.citation: J Neurochem. 1996 May;66(5):1836-44
references.pmid: 8780008
references.citation: Curr Pharm Des. 2006;12(12):1505-20
references.pmid: 16611131
references.citation: Neurology. 1997 May;48(5 Suppl 7):S8-15
references.pmid: 9153161
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9287-92
references.pmid: 10922077
references.citation: Endocrinology. 1997 Nov;138(11):5067-70
references.pmid: 9348242
references.citation: Mol Endocrinol. 1997 Sep;11(10):1486-96
references.pmid: 9280064
references.citation: Psychoneuroendocrinology. 1992 Oct;17(5):485-95
references.pmid: 1484915
references.citation: Genes Brain Behav. 2006 Oct;5(7):528-39
references.pmid: 17010099
references.citation: Postgrad Med. 2001 Mar;Spec No:11-6
references.pmid: 11296734
references.citation: Mol Hum Reprod. 2007 Aug;13(8):537-40
references.pmid: 17556378
references.citation: Neurosci Lett. 2001 Aug 31;309(3):207-9
references.pmid: 11514077
references.citation: Brain Res Mol Brain Res. 1998 Mar 30;55(1):169-72
references.pmid: 9645972
references.citation: J Comp Neurol. 2002 May 20;447(1):34-42
references.pmid: 11967893
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9956-61
references.pmid: 9275233