title: Progesterone influence on neurite outgrowth involves microglia.
abstract: Progesterone (P4) antagonizes estradiol (E2) in synaptic remodeling in the hippocampus during the rat estrous cycle. To further understand how P4 modulates synaptic plasticity, we used entorhinal cortex lesions, which induce E2-dependent neurite sprouting in the hippocampus. In young ovariectomized rats, the E2-dependent entorhinal cortex lesion-induced sprouting was attenuated by concurrent treatment with P4 and E2. Microglial activation also showed the E2-P4 antagonism. These findings extend reports on the estrous cycle synaptic remodeling without lesions by showing the P4-E2 antagonism during simultaneous treatment with both E2 and P4. Glial mechanisms were analyzed with the wounding-in-a-dish model of cocultured glia and embryonic d-18 cortical neurons from rat. In cocultures of mixed glia (astrocytes plus 30% microglia), P4 antagonized the E2-dependent neurite outgrowth (number and length) and neuron viability in the presence of E2, as observed in vivo. However, removal of microglia (astrocyte-neuron coculture) abolished the antagonism of E2 by P4 on neuron sprouting. The P4 receptor antagonists ORG-31710 and RU-486 blocked the antagonism of P4 on E2-dependent sprouting. These findings suggest a new role for microglia in P4 antagonism of E2 in neuronal plasticity and show its dependence on progesterone receptors. These findings are also relevant to the inclusion of progestins in hormone therapy, which is controversial in relation to cognitive declines during aging and in Alzheimer's disease.
authors.affiliation: Biogerontology Division, Davis School of Gerontology, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Wong
authors.forename: Irina
authors.initials: I
authors.lastname: Rozovsky
authors.forename: Jason M
authors.initials: JM
authors.lastname: Arimoto
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Du
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Todd E
authors.initials: TE
authors.lastname: Morgan
authors.forename: Caleb E
authors.initials: CE
authors.lastname: Finch
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018929:Cell Culture Techniques; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D013569:Synapses / Q000187:drug effects / Q000502:physiology
chemical_list: D004965:Estrogen Antagonists; D011374:Progesterone; D004958:Estradiol
references.citation: Brain Res. 2006 Jul 12;1099(1):206-10
references.pmid: 16793026
references.citation: Science. 1985 Dec 6;230(4730):1179-81
references.pmid: 4071042
references.citation: J Endocrinol Invest. 2000 Mar;23(3):151-7
references.pmid: 10803471
references.citation: Brain Res. 2004 Jul 23;1015(1-2):169-74
references.pmid: 15223381
references.citation: Endocrinology. 1998 Jul;139(7):3202-9
references.pmid: 9645694
references.citation: J Neurosci. 2002 May 15;22(10):4095-102
references.pmid: 12019328
references.citation: Exp Neurol. 2000 Sep;165(1):46-57
references.pmid: 10964484
references.citation: Neuroscience. 1999;91(3):1009-16
references.pmid: 10391478
references.citation: Hippocampus. 1997;7(3):341-9
references.pmid: 9228530
references.citation: Exp Cell Res. 2005 Oct 1;309(2):305-15
references.pmid: 16038898
references.citation: J Peripher Nerv Syst. 2006 Jun;11(2):111-8
references.pmid: 16787508
references.citation: Eur J Neurosci. 1999 Sep;11(9):3359-64
references.pmid: 10510203
references.citation: Exp Neurol. 1992 Oct;118(1):47-52
references.pmid: 1397175
references.citation: J Biol Chem. 1994 Apr 22;269(16):11945-9
references.pmid: 8163495
references.citation: J Neurosci. 1999 Nov 15;19(22):RC42
references.pmid: 10559432
references.citation: Brain Res. 2005 Jul 5;1049(1):112-9
references.pmid: 15932748
references.citation: J Comp Neurol. 2007 Sep 1;504(1):42-56
references.pmid: 17614295
references.citation: Hum Reprod. 1994 Jun;9 Suppl 1:77-81
references.pmid: 7962474
references.citation: Ann Emerg Med. 2007 Apr;49(4):391-402, 402.e1-2
references.pmid: 17011666
references.citation: Endocrinology. 2006 Nov;147(11):5303-13
references.pmid: 16916950
references.citation: Endocr Rev. 2007 Jun;28(4):387-439
references.pmid: 17431228
references.citation: Science. 1984 Sep 21;225(4668):1287-94
references.pmid: 6382610
references.citation: Brain Res. 1980 May 19;190(1):195-214
references.pmid: 6769533
references.citation: Menopause. 2007 May-Jun;14(3 Pt 2):572-9
references.pmid: 17476147
references.citation: JAMA. 2004 Jun 23;291(24):2947-58
references.pmid: 15213206
references.citation: J Comp Neurol. 1979 Feb 1;183(3):539-49
references.pmid: 759447
references.citation: FASEB J. 2003 Jun;17(9):1110-1
references.pmid: 12692086
references.citation: Hum Reprod. 1994 Jun;9 Suppl 1:47-52
references.pmid: 7962469
references.citation: Neurobiol Aging. 1998 Jan-Feb;19(1):97-103
references.pmid: 9562510
references.citation: J Cell Biol. 1980 Jun;85(3):890-902
references.pmid: 6248568
references.citation: Neurobiol Aging. 2005 May;26(5):705-15
references.pmid: 15708446
references.citation: JAMA. 2003 May 28;289(20):2651-62
references.pmid: 12771112
references.citation: Front Neuroendocrinol. 2008 May;29(2):313-39
references.pmid: 18374402
references.citation: J Clin Endocrinol Metab. 2006 May;91(5):1802-10
references.pmid: 16522699
references.citation: J Neurosci. 1997 Jun 1;17(11):4121-8
references.pmid: 9151729
references.citation: Br J Clin Pharmacol. 1992 Mar;33(3):293-8
references.pmid: 1576050
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15512-7
references.pmid: 8986843
references.citation: J Neurochem. 2006 Nov;99(4):1263-72
references.pmid: 16981890
references.citation: Neurobiol Aging. 2005 Nov-Dec;26(10):1365-74
references.pmid: 16243607
references.citation: Neurosci Lett. 2008 May 30;437(2):116-20
references.pmid: 18439758
references.citation: Brain Res Brain Res Rev. 2005 Apr;48(2):273-86
references.pmid: 15850667
references.citation: Glia. 2008 Apr 15;56(6):659-74
references.pmid: 18286612
references.citation: Exp Gerontol. 1994 May-Aug;29(3-4):431-6
references.pmid: 7925761
references.citation: J Comp Neurol. 1993 Oct 8;336(2):293-306
references.pmid: 8245220
references.citation: J Neurosci Res. 2004 Jan 15;75(2):203-17
references.pmid: 14705141
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10041-5
references.pmid: 16785436
references.citation: Endocrinology. 2002 Feb;143(2):636-46
references.pmid: 11796520
references.citation: Neurosci Lett. 2006 May 8;398(3):337-42
references.pmid: 16472911
references.citation: Brain Dev. 1998 Mar;20(2):88-94
references.pmid: 9545178
references.citation: Glia. 2008 Feb;56(3):259-70
references.pmid: 18069670
references.citation: Exp Neurol. 1997 Feb;143(2):313-8
references.pmid: 9056393
references.citation: Trends Neurosci. 1994 Apr;17(4):138-42
references.pmid: 7517589
references.citation: Restor Neurol Neurosci. 2000;16(2):87-96
references.pmid: 12671211
references.citation: Curr Med Chem. 2007;14(27):2865-71
references.pmid: 18045132
references.citation: JAMA. 2004 Jun 23;291(24):2959-68
references.pmid: 15213207
references.citation: Front Biosci. 2008 Jan 01;13:1083-9
references.pmid: 17981614
references.citation: J Anat. 1942 Oct;77(Pt 1):63-96.10
references.pmid: 17104917
references.citation: Am J Physiol Renal Physiol. 2006 Feb;290(2):F306-12
references.pmid: 16189295
references.citation: J Neurosci. 2002 May 1;22(9):3484-92
references.pmid: 11978825
references.citation: Neuroscience. 2005;133(2):423-36
references.pmid: 15878805
references.citation: J Appl Physiol (1985). 2001 Dec;91(6):2785-801
references.pmid: 11717247
references.citation: J Neurosci. 2007 Nov 28;27(48):13357-65
references.pmid: 18045930
references.citation: Endocrinology. 2003 Nov;144(11):4734-8
references.pmid: 12960039
references.citation: JAMA. 2003 May 28;289(20):2663-72
references.pmid: 12771113
references.citation: Front Neuroendocrinol. 2008 Jan;29(1):88-113
references.pmid: 17980408
references.citation: Neuroreport. 2002 May 7;13(6):825-30
references.pmid: 11997695
references.citation: J Neurosci. 2007 Oct 17;27(42):11416-23
references.pmid: 17942736
references.citation: Brain Res. 2004 May 15;1008(1):29-39
references.pmid: 15081379