title: Ovarian steroids increase PSD-95 expression and dendritic spines in the dorsal raphe of ovariectomized macaques.
abstract: Estradiol (E) and progesterone (P) promote spinogenesis in several brain areas. Intracellular signaling cascades that promote spinogenesis involve RhoGTPases, glutamate signaling and synapse assembly. We found that in serotonin neurons, E ± P administration increases (a) gene and protein expression of RhoGTPases, (b) gene expression of glutamate receptors, and (c) gene expression of pivotal synapse assembly proteins. Therefore, in this study we determined whether structural changes in dendritic spines in the dorsal raphe follow the observed changes in gene and protein expression. Dendritic spines were examined with immunogold silver staining of a spine marker protein, postsynaptic density-95 (PSD-95) and with Golgi staining. In the PSD-95 study, adult Ovx monkeys received placebo, E, P, or E + P for 1 month (n = 3/group). Sections were immunostained for PSD-95 and the number of PSD-95-positive puncta was determined with stereology. E, P, and E + P treatment significantly increased the total number of PSD-95-positive puncta (ANOVA, P = 0.04). In the golgi study, adult Ovx monkeys received placebo, E or E + P for 1 month (n = 3-4) and the midbrain was golgi-stained. A total of 80 neurons were analyzed with Neurolucida software. There was a significant difference in spine density that depended on branch order (two-way ANOVA). E + P treatment significantly increased spine density in higher-order (3°-5°) dendritic branches relative to Ovx group (Bonferroni, P < 0.05). In summary, E + P leads to the elaboration of dendritic spines on dorsal raphe neurons. The ability of E to induce PSD-95, but not actual spines, suggests either a sampling or time lag issue. Increased spinogenesis on serotonin dendrites would facilitate excitatory glutamatergic input and, in turn, increase serotonin neurotransmission throughout the brain.
authors: Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, Oregon, 97006.
authors: Heidi M
authors: HM
authors: Rivera
authors: Cynthia L
authors: CL
authors: Bethea
mesh_terms: D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004958:Estradiol / Q000172:deficiency / Q000494:pharmacology*; D005260:Female; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008253:Macaca mulatta; D010052:Ovariectomy; D011374:Progesterone / Q000172:deficiency / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D059326:Serotonergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011374:Progesterone; D004958:Estradiol
keywords: dendritic spines; estradiol; golgi; progesterone; serotonin
references: J Neurosci. 2003 Jan 15;23(2):659-65
references: 12533625
references: Biol Psychiatry. 1998 Nov 1;44(9):798-811
references: 9807636
references: Nat Neurosci. 1999 Jan;2(1):44-9
references: 10195179
references: J Neurochem. 2008 May;105(4):1129-43
references: 18182058
references: J Neurosci. 1992 Jul;12(7):2549-54
references: 1613547
references: J Neurosci. 2003 Mar 15;23(6):2333-9
references: 12657692
references: Endocrinology. 2001 Mar;142(3):1284-9
references: 11181546
references: J Clin Endocrinol Metab. 1991 Feb;72(2):336-43
references: 1846872
references: Neuroendocrinology. 1990 May;51(5):530-5
references: 2112730
references: J Neurosci Methods. 2012 Aug 15;209(2):269-79
references: 22750653
references: Anat Rec. 1991 Dec;231(4):482-97
references: 1793176
references: Biol Psychiatry. 2003 Apr 15;53(8):707-42
references: 12706957
references: Nat Neurosci. 2008 Mar;11(3):334-43
references: 18297067
references: Prog Neurobiol. 2005 Feb;75(3):161-205
references: 15882774
references: Mol Psychiatry. 2003 Mar;8(3):353-60
references: 12660809
references: Science. 1986 May 23;232(4753):1004-7
references: 2422758
references: Hippocampus. 2007;17(11):1017-22
references: 17636549
references: Mol Psychiatry. 2010 Jun;15(6):657-68
references: 19823180
references: Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):194-203
references: 15857682
references: Am J Psychiatry. 2004 Dec;161(12):2238-44
references: 15569895
references: Mol Psychiatry. 2010 Oct;15(10):1034-44
references: 19687787
references: Science. 2000 Nov 17;290(5495):1364-8
references: 11082065
references: J Neurosci. 1990 Apr;10(4):1286-91
references: 2329377
references: Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19902-7
references: 17179037
references: Neuroscience. 2012 Apr 19;208:27-40
references: 22342969
references: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11412-7
references: 9736750
references: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2185-90
references: 14766964
references: PLoS One. 2008 Apr 23;3(4):e1997
references: 18431482
references: Nat Protoc. 2011 Aug 25;6(9):1391-411
references: 21886104
references: Brain Res. 2008 Nov 13;1240:73-81
references: 18809393
references: Front Neuroendocrinol. 2002 Jan;23(1):41-100
references: 11906203
references: Drugs Aging. 2003;20(2):85-100
references: 12534310
references: Neuron. 2006 Jul 6;51(1):99-111
references: 16815335
references: Brain Res Mol Brain Res. 2001 Jul 13;91(1-2):14-22
references: 11457488
references: Neuroscience. 2005;132(1):151-66
references: 15780474
references: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2237-42
references: 12601167
references: Psychosom Med. 1999 Sep-Oct;61(5):676-97
references: 10511016
references: Front Neuroendocrinol. 2009 Jul;30(2):212-38
references: 19394356
references: J Br Menopause Soc. 2006 Sep;12(3):115-25
references: 16953985
references: Physiol Rev. 1992 Jan;72(1):165-229
references: 1731370
references: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11465-70
references: 17592140
references: PLoS Biol. 2008 Sep 9;6(9):e219
references: 18788894
references: J Neurosci Res. 2012 Jul;90(7):1324-34
references: 22411564
references: Am J Psychiatry. 2003 Aug;160(8):1522-4
references: 12900319
references: J Comp Neurol. 2003 Oct 27;465(4):540-50
references: 12975814
references: J Psychiatry Neurosci. 2006 Mar;31(2):105-14
references: 16575426
references: Depress Anxiety. 2000;12 Suppl 1:2-19
references: 11098410
references: Psychopharmacology (Berl). 2002 Mar;160(3):271-82
references: 11889496
references: Dev Neurosci. 1998;20(2-3):253-62
references: 9691199
references: Neuropsychopharmacology. 2002 Jul;27(1):12-24
references: 12062903
references: Hum Reprod. 1994 Jun;9 Suppl 1:82-97
references: 7962475
references: Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13902-7
references: 12359873
references: J Neurosci. 2009 Oct 14;29(41):12982-93
references: 19828812
references: Neuroendocrinology. 1993 Jan;57(1):1-6
references: 8479605
references: Nat Rev Neurosci. 2004 Jan;5(1):24-34
references: 14708001
references: Brain Res. 2009 Sep 22;1290:1-11
references: 19596275
references: Neuroendocrinology. 1994 Jul;60(1):50-61
references: 8090282
references: J Neurosci. 2007 Jul 11;27(28):7408-17
references: 17626201
references: Eur J Biochem. 1996 Aug 1;239(3):726-31
references: 8774719
references: J Neurosci. 2006 Mar 1;26(9):2571-8
references: 16510735
references: Neuroscience. 2011 Sep 29;192:675-88
references: 21763405
references: Endocrinology. 2003 Nov;144(11):4734-8
references: 12960039
references: Science. 1995 Sep 22;269(5231):1737-40
references: 7569905
references: Mol Cell Neurosci. 2012 Mar;49(3):251-62
references: 22154832
references: Neuroscience. 2008 Sep 9;155(4):1106-19
references: 18601981
references: Behav Brain Res. 2011 Nov 20;225(1):317-27
references: 21835209
references: Hippocampus. 2000;10(5):501-11
references: 11075821
references: Nature. 1998 Dec 3;396(6710):433-9
references: 9853749
references: J Comp Neurol. 2002 May 20;447(1):34-42
references: 11967893
references: J Comp Neurol. 2000 Oct 30;426(4):572-86
references: 11027400
references: Biol Reprod. 1982 Mar;26(2):241-8
references: 6802194