Chronic estrogen deficiency leads to molecular aberrations related to neurodegenerative changes in follitropin receptor knockout female mice
The follitropin receptor knockout (FORKO) mouse undergoes ovarian failure, thereby providing an animal model to investigate the consequences of the depletion of circulating estrogen in females. The estrogen deficiency causes marked defects in the female reproductive system, obesity, and skeletal abn...
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| Veröffentlicht in: | Neuroscience 2002-01, Vol.114 (2), p.493-506 |
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| description | The follitropin receptor knockout (FORKO) mouse undergoes ovarian failure, thereby providing an animal model to investigate the consequences of the depletion of circulating estrogen in females. The estrogen deficiency causes marked defects in the female reproductive system, obesity, and skeletal abnormalities. In light of estrogen’s known pleiotropic effects in the nervous system, our study examined the effects of genetically induced estrogen–testosterone imbalance on this system in female FORKO mice. Circulating concentrations of 17-β-estradiol (E2) in FORKO mice are significantly decreased (FORKO −/−: 1.13±0.34 pg/ml; wild-type +/+: 17.6±3.5 pg/ml,
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| doi_str_mv | 10.1016/S0306-4522(02)00278-6 |
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P<0.0001,
n=32–41); in contrast, testosterone levels are increased (−/−: 37.7±2.3 pg/ml; wild-type +/+: 3.9±1.7 pg/ml,
P<0.005,
n=25–33). The focus was on the activities of key enzymes in the central cholinergic and peripheral nervous systems, on dorsal root ganglia (DRGs) capacity for neurite outgrowth, and on the phosphorylation state of structural neurofilament (NF) proteins. Choline acetyltransferase activity was decreased in several central cholinergic structures (striatum 50±3%, hippocampus 24±2%, cortex 12±3%) and in DRGs (11±6%). Moreover, we observed aberrations in the enzymatic activities of mitogen-activated protein kinases (extracellular-regulated kinase and c-Jun N-terminal kinase) in the hippocampus, DRGs, and sciatic nerves. Hippocampal and sensory ganglia samples from FORKO mice contained hyper-phosphorylated NFs. Finally, explanted ganglia of FORKO mice displayed decreased neurite outgrowth (20–50%) under non-treated conditions and when treated with E2 (10 nM). Our results demonstrate that genetic depletion of circulating estrogen leads to biochemical and morphological changes in central and peripheral neurons, and underlie the importance of estrogen in the normal development and functioning of the nervous system. In particular, the findings suggest that an early and persisting absence of the steroid leads to neurodegenerative changes and identify several key enzymes that may contribute to the process. This model provides a system to explore the consequences of circulating estrogen deprivation and other hormonal imbalances in the nervous system.</description><identifier>ISSN: 0306-4522</identifier><identifier>EISSN: 1873-7544</identifier><identifier>DOI: 10.1016/S0306-4522(02)00278-6</identifier><identifier>PMID: 12204217</identifier><identifier>CODEN: NRSCDN</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Acetylcholine - metabolism ; Animals ; Biological and medical sciences ; Cell Differentiation - drug effects ; Cell Differentiation - genetics ; Cells, Cultured ; Central Nervous System - metabolism ; Central Nervous System - pathology ; Central Nervous System - physiopathology ; choline acetyltransferase ; Choline O-Acetyltransferase - metabolism ; CNS ; dorsal root ganglia ; Enzyme Inhibitors - pharmacology ; estrogen ; Estrogens - deficiency ; Estrogens - metabolism ; Estrogens - pharmacology ; Female ; follicle stimulating hormone ; Fundamental and applied biological sciences. Psychology ; Ganglia, Spinal - cytology ; Ganglia, Spinal - drug effects ; Ganglia, Spinal - growth & development ; General aspects. Hormone interactions. Hormone actions on several organ systems. Adaptive reactions ; Mice ; Mice, Knockout ; mitogen-activated protein kinase ; Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Mitogen-Activated Protein Kinases - metabolism ; Neurites - drug effects ; Neurites - ultrastructure ; Neurodegenerative Diseases - etiology ; Neurodegenerative Diseases - metabolism ; Neurodegenerative Diseases - physiopathology ; neurofilament ; Neurofilament Proteins - metabolism ; Peripheral Nervous System - metabolism ; Peripheral Nervous System - pathology ; Peripheral Nervous System - physiopathology ; Receptors, FSH - deficiency ; Receptors, FSH - genetics ; Testosterone - metabolism ; Up-Regulation - genetics ; Vertebrates: endocrinology</subject><ispartof>Neuroscience, 2002-01, Vol.114 (2), p.493-506</ispartof><rights>2002 IBRO</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-f5669c0e898d792ff2e2601b1302515d8b34b3f201530521fde36465402ea4013</citedby><cites>FETCH-LOGICAL-c422t-f5669c0e898d792ff2e2601b1302515d8b34b3f201530521fde36465402ea4013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0306-4522(02)00278-6$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13906641$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12204217$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tam, J</creatorcontrib><creatorcontrib>Danilovich, N</creatorcontrib><creatorcontrib>Nilsson, K</creatorcontrib><creatorcontrib>Sairam, M.R</creatorcontrib><creatorcontrib>Maysinger, D</creatorcontrib><title>Chronic estrogen deficiency leads to molecular aberrations related to neurodegenerative changes in follitropin receptor knockout female mice</title><title>Neuroscience</title><addtitle>Neuroscience</addtitle><description>The follitropin receptor knockout (FORKO) mouse undergoes ovarian failure, thereby providing an animal model to investigate the consequences of the depletion of circulating estrogen in females. The estrogen deficiency causes marked defects in the female reproductive system, obesity, and skeletal abnormalities. In light of estrogen’s known pleiotropic effects in the nervous system, our study examined the effects of genetically induced estrogen–testosterone imbalance on this system in female FORKO mice. Circulating concentrations of 17-β-estradiol (E2) in FORKO mice are significantly decreased (FORKO −/−: 1.13±0.34 pg/ml; wild-type +/+: 17.6±3.5 pg/ml,
P<0.0001,
n=32–41); in contrast, testosterone levels are increased (−/−: 37.7±2.3 pg/ml; wild-type +/+: 3.9±1.7 pg/ml,
P<0.005,
n=25–33). The focus was on the activities of key enzymes in the central cholinergic and peripheral nervous systems, on dorsal root ganglia (DRGs) capacity for neurite outgrowth, and on the phosphorylation state of structural neurofilament (NF) proteins. Choline acetyltransferase activity was decreased in several central cholinergic structures (striatum 50±3%, hippocampus 24±2%, cortex 12±3%) and in DRGs (11±6%). Moreover, we observed aberrations in the enzymatic activities of mitogen-activated protein kinases (extracellular-regulated kinase and c-Jun N-terminal kinase) in the hippocampus, DRGs, and sciatic nerves. Hippocampal and sensory ganglia samples from FORKO mice contained hyper-phosphorylated NFs. Finally, explanted ganglia of FORKO mice displayed decreased neurite outgrowth (20–50%) under non-treated conditions and when treated with E2 (10 nM). Our results demonstrate that genetic depletion of circulating estrogen leads to biochemical and morphological changes in central and peripheral neurons, and underlie the importance of estrogen in the normal development and functioning of the nervous system. In particular, the findings suggest that an early and persisting absence of the steroid leads to neurodegenerative changes and identify several key enzymes that may contribute to the process. This model provides a system to explore the consequences of circulating estrogen deprivation and other hormonal imbalances in the nervous system.</description><subject>Acetylcholine - metabolism</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Differentiation - genetics</subject><subject>Cells, Cultured</subject><subject>Central Nervous System - metabolism</subject><subject>Central Nervous System - pathology</subject><subject>Central Nervous System - physiopathology</subject><subject>choline acetyltransferase</subject><subject>Choline O-Acetyltransferase - metabolism</subject><subject>CNS</subject><subject>dorsal root ganglia</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>estrogen</subject><subject>Estrogens - deficiency</subject><subject>Estrogens - metabolism</subject><subject>Estrogens - pharmacology</subject><subject>Female</subject><subject>follicle stimulating hormone</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Ganglia, Spinal - cytology</subject><subject>Ganglia, Spinal - drug effects</subject><subject>Ganglia, Spinal - growth & development</subject><subject>General aspects. Hormone interactions. Hormone actions on several organ systems. Adaptive reactions</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>mitogen-activated protein kinase</subject><subject>Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Neurites - drug effects</subject><subject>Neurites - ultrastructure</subject><subject>Neurodegenerative Diseases - etiology</subject><subject>Neurodegenerative Diseases - metabolism</subject><subject>Neurodegenerative Diseases - physiopathology</subject><subject>neurofilament</subject><subject>Neurofilament Proteins - metabolism</subject><subject>Peripheral Nervous System - metabolism</subject><subject>Peripheral Nervous System - pathology</subject><subject>Peripheral Nervous System - physiopathology</subject><subject>Receptors, FSH - deficiency</subject><subject>Receptors, FSH - genetics</subject><subject>Testosterone - metabolism</subject><subject>Up-Regulation - genetics</subject><subject>Vertebrates: endocrinology</subject><issn>0306-4522</issn><issn>1873-7544</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkd1uFSEUhYnR2NPqI2i40dSLUf5nzlVjTvxLmnihXhMGNi2WgSPMNOk7-NAyPSf2soQEEr699mYthF5R8p4Sqj78IJyoTkjGzgl7Rwjrh049QRs69LzrpRBP0eY_coJOa_1N2pKCP0cnlDEiGO036O_uuuQULIY6l3wFCTvwwQZI9g5HMK7iOeMpR7BLNAWbEUoxc8ip4gLRzOBWIMFSsoNWD-vrLWB7bdIVVBwS9jnG0NT37V7Awn7OBd-kbG_yMmMPk4mAp2DhBXrmTazw8nieoV-fP_3cfe0uv3_5tvt42VnB2Nx5qdTWEhi2g-u3zHsGTBE6Uk6YpNINIxcj94xQyYlk1DvgSigpCAMjCOVn6O1Bd1_yn6X9XE-hWojRJMhL1T1rPjFJHgXpoMTQb1dFeQBtybUW8HpfwmTKnaZEr3np-7z0GoYmba95adXqXh8bLOME7qHqGFAD3hwBU62JvphkQ33g-JYoJdYBLg4cNN9uAxRd70MEF5rls3Y5PDLKPztJs58</recordid><startdate>20020101</startdate><enddate>20020101</enddate><creator>Tam, J</creator><creator>Danilovich, N</creator><creator>Nilsson, K</creator><creator>Sairam, M.R</creator><creator>Maysinger, D</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>20020101</creationdate><title>Chronic estrogen deficiency leads to molecular aberrations related to neurodegenerative changes in follitropin receptor knockout female mice</title><author>Tam, J ; Danilovich, N ; Nilsson, K ; Sairam, M.R ; Maysinger, D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-f5669c0e898d792ff2e2601b1302515d8b34b3f201530521fde36465402ea4013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Acetylcholine - metabolism</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Differentiation - genetics</topic><topic>Cells, Cultured</topic><topic>Central Nervous System - metabolism</topic><topic>Central Nervous System - pathology</topic><topic>Central Nervous System - physiopathology</topic><topic>choline acetyltransferase</topic><topic>Choline O-Acetyltransferase - metabolism</topic><topic>CNS</topic><topic>dorsal root ganglia</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>estrogen</topic><topic>Estrogens - deficiency</topic><topic>Estrogens - metabolism</topic><topic>Estrogens - pharmacology</topic><topic>Female</topic><topic>follicle stimulating hormone</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Ganglia, Spinal - cytology</topic><topic>Ganglia, Spinal - drug effects</topic><topic>Ganglia, Spinal - growth & development</topic><topic>General aspects. Hormone interactions. Hormone actions on several organ systems. Adaptive reactions</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>mitogen-activated protein kinase</topic><topic>Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Neurites - drug effects</topic><topic>Neurites - ultrastructure</topic><topic>Neurodegenerative Diseases - etiology</topic><topic>Neurodegenerative Diseases - metabolism</topic><topic>Neurodegenerative Diseases - physiopathology</topic><topic>neurofilament</topic><topic>Neurofilament Proteins - metabolism</topic><topic>Peripheral Nervous System - metabolism</topic><topic>Peripheral Nervous System - pathology</topic><topic>Peripheral Nervous System - physiopathology</topic><topic>Receptors, FSH - deficiency</topic><topic>Receptors, FSH - genetics</topic><topic>Testosterone - metabolism</topic><topic>Up-Regulation - genetics</topic><topic>Vertebrates: endocrinology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tam, J</creatorcontrib><creatorcontrib>Danilovich, N</creatorcontrib><creatorcontrib>Nilsson, K</creatorcontrib><creatorcontrib>Sairam, M.R</creatorcontrib><creatorcontrib>Maysinger, D</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tam, J</au><au>Danilovich, N</au><au>Nilsson, K</au><au>Sairam, M.R</au><au>Maysinger, D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chronic estrogen deficiency leads to molecular aberrations related to neurodegenerative changes in follitropin receptor knockout female mice</atitle><jtitle>Neuroscience</jtitle><addtitle>Neuroscience</addtitle><date>2002-01-01</date><risdate>2002</risdate><volume>114</volume><issue>2</issue><spage>493</spage><epage>506</epage><pages>493-506</pages><issn>0306-4522</issn><eissn>1873-7544</eissn><coden>NRSCDN</coden><abstract>The follitropin receptor knockout (FORKO) mouse undergoes ovarian failure, thereby providing an animal model to investigate the consequences of the depletion of circulating estrogen in females. The estrogen deficiency causes marked defects in the female reproductive system, obesity, and skeletal abnormalities. In light of estrogen’s known pleiotropic effects in the nervous system, our study examined the effects of genetically induced estrogen–testosterone imbalance on this system in female FORKO mice. Circulating concentrations of 17-β-estradiol (E2) in FORKO mice are significantly decreased (FORKO −/−: 1.13±0.34 pg/ml; wild-type +/+: 17.6±3.5 pg/ml,
P<0.0001,
n=32–41); in contrast, testosterone levels are increased (−/−: 37.7±2.3 pg/ml; wild-type +/+: 3.9±1.7 pg/ml,
P<0.005,
n=25–33). The focus was on the activities of key enzymes in the central cholinergic and peripheral nervous systems, on dorsal root ganglia (DRGs) capacity for neurite outgrowth, and on the phosphorylation state of structural neurofilament (NF) proteins. Choline acetyltransferase activity was decreased in several central cholinergic structures (striatum 50±3%, hippocampus 24±2%, cortex 12±3%) and in DRGs (11±6%). Moreover, we observed aberrations in the enzymatic activities of mitogen-activated protein kinases (extracellular-regulated kinase and c-Jun N-terminal kinase) in the hippocampus, DRGs, and sciatic nerves. Hippocampal and sensory ganglia samples from FORKO mice contained hyper-phosphorylated NFs. Finally, explanted ganglia of FORKO mice displayed decreased neurite outgrowth (20–50%) under non-treated conditions and when treated with E2 (10 nM). Our results demonstrate that genetic depletion of circulating estrogen leads to biochemical and morphological changes in central and peripheral neurons, and underlie the importance of estrogen in the normal development and functioning of the nervous system. In particular, the findings suggest that an early and persisting absence of the steroid leads to neurodegenerative changes and identify several key enzymes that may contribute to the process. This model provides a system to explore the consequences of circulating estrogen deprivation and other hormonal imbalances in the nervous system.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>12204217</pmid><doi>10.1016/S0306-4522(02)00278-6</doi><tpages>14</tpages></addata></record> |
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| subjects | Acetylcholine - metabolism Animals Biological and medical sciences Cell Differentiation - drug effects Cell Differentiation - genetics Cells, Cultured Central Nervous System - metabolism Central Nervous System - pathology Central Nervous System - physiopathology choline acetyltransferase Choline O-Acetyltransferase - metabolism CNS dorsal root ganglia Enzyme Inhibitors - pharmacology estrogen Estrogens - deficiency Estrogens - metabolism Estrogens - pharmacology Female follicle stimulating hormone Fundamental and applied biological sciences. Psychology Ganglia, Spinal - cytology Ganglia, Spinal - drug effects Ganglia, Spinal - growth & development General aspects. Hormone interactions. Hormone actions on several organ systems. Adaptive reactions Mice Mice, Knockout mitogen-activated protein kinase Mitogen-Activated Protein Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinases - metabolism Neurites - drug effects Neurites - ultrastructure Neurodegenerative Diseases - etiology Neurodegenerative Diseases - metabolism Neurodegenerative Diseases - physiopathology neurofilament Neurofilament Proteins - metabolism Peripheral Nervous System - metabolism Peripheral Nervous System - pathology Peripheral Nervous System - physiopathology Receptors, FSH - deficiency Receptors, FSH - genetics Testosterone - metabolism Up-Regulation - genetics Vertebrates: endocrinology |
| title | Chronic estrogen deficiency leads to molecular aberrations related to neurodegenerative changes in follitropin receptor knockout female mice |
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