Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome
This study shows that the interaction between metabotropic glutamate receptor 5 (mGluR5) and a specific form of the scaffolding protein Homer contributes to the behavioral and physiological defects in the mouse model of fragile X syndrome. Enhanced metabotropic glutamate receptor subunit 5 (mGluR5)...
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| Veröffentlicht in: | Nature neuroscience 2012-03, Vol.15 (3), p.431-440 |
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| container_title | Nature neuroscience |
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| creator | Ronesi, Jennifer A Collins, Katie A Hays, Seth A Tsai, Nien-Pei Guo, Weirui Birnbaum, Shari G Hu, Jia-Hua Worley, Paul F Gibson, Jay R Huber, Kimberly M |
| description | This study shows that the interaction between metabotropic glutamate receptor 5 (mGluR5) and a specific form of the scaffolding protein Homer contributes to the behavioral and physiological defects in the mouse model of fragile X syndrome.
Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model,
Fmr1
knockout (
Fmr1
−/
y
). In
Fmr1
−/
y
mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5–long Homer scaffolds and corrected several phenotypes in
Fmr1
−/
y
mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many
Fmr1
−/
y
phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of
Fmr1
. Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism. |
| doi_str_mv | 10.1038/nn.3033 |
| format | Article |
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Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model,
Fmr1
knockout (
Fmr1
−/
y
). In
Fmr1
−/
y
mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5–long Homer scaffolds and corrected several phenotypes in
Fmr1
−/
y
mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many
Fmr1
−/
y
phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of
Fmr1
. Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.</description><identifier>ISSN: 1097-6256</identifier><identifier>EISSN: 1546-1726</identifier><identifier>DOI: 10.1038/nn.3033</identifier><identifier>PMID: 22267161</identifier><identifier>CODEN: NANEFN</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/378/1689 ; 631/378/340 ; Analysis of Variance ; Animal Genetics and Genomics ; Animals ; Behavioral Sciences ; Biological Techniques ; Biomedical and Life Sciences ; Biomedicine ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cycloheximide - pharmacology ; Disease Models, Animal ; Electric Stimulation - methods ; Exploratory Behavior - physiology ; Fragile X Mental Retardation Protein ; Fragile X syndrome ; Fragile X Syndrome - genetics ; Fragile X Syndrome - metabolism ; Fragile X Syndrome - pathology ; Fragile X Syndrome - physiopathology ; Gene Expression Regulation - genetics ; Gene Expression Regulation - physiology ; Gene mutations ; Genetic aspects ; Health aspects ; Hippocampus - pathology ; Hippocampus - physiopathology ; Homer Scaffolding Proteins ; Immunoprecipitation ; In Vitro Techniques ; Long-Term Potentiation - drug effects ; Long-Term Potentiation - genetics ; Methoxyhydroxyphenylglycol - analogs & derivatives ; Methoxyhydroxyphenylglycol - pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Nerve Net - drug effects ; Nerve Net - physiology ; Neurobiology ; Neurosciences ; Neurotransmitter receptors ; Patch-Clamp Techniques ; Peptides - pharmacology ; Physics ; Physiological aspects ; Protein Synthesis Inhibitors - pharmacology ; Rats ; Rats, Long-Evans ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate - chemistry ; Receptors, Metabotropic Glutamate - metabolism ; Risk factors ; Serine - metabolism ; Signal Transduction - drug effects ; Signal Transduction - genetics ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>Nature neuroscience, 2012-03, Vol.15 (3), p.431-440</ispartof><rights>Springer Nature America, Inc. 2012</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Mar 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-ab766133226988324c4f09ce0cdde58f4266181451c6136a65f421a37b15ec003</citedby><cites>FETCH-LOGICAL-c508t-ab766133226988324c4f09ce0cdde58f4266181451c6136a65f421a37b15ec003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nn.3033$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nn.3033$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22267161$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ronesi, Jennifer A</creatorcontrib><creatorcontrib>Collins, Katie A</creatorcontrib><creatorcontrib>Hays, Seth A</creatorcontrib><creatorcontrib>Tsai, Nien-Pei</creatorcontrib><creatorcontrib>Guo, Weirui</creatorcontrib><creatorcontrib>Birnbaum, Shari G</creatorcontrib><creatorcontrib>Hu, Jia-Hua</creatorcontrib><creatorcontrib>Worley, Paul F</creatorcontrib><creatorcontrib>Gibson, Jay R</creatorcontrib><creatorcontrib>Huber, Kimberly M</creatorcontrib><title>Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome</title><title>Nature neuroscience</title><addtitle>Nat Neurosci</addtitle><addtitle>Nat Neurosci</addtitle><description>This study shows that the interaction between metabotropic glutamate receptor 5 (mGluR5) and a specific form of the scaffolding protein Homer contributes to the behavioral and physiological defects in the mouse model of fragile X syndrome.
Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model,
Fmr1
knockout (
Fmr1
−/
y
). In
Fmr1
−/
y
mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5–long Homer scaffolds and corrected several phenotypes in
Fmr1
−/
y
mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many
Fmr1
−/
y
phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of
Fmr1
. Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.</description><subject>631/378/1689</subject><subject>631/378/340</subject><subject>Analysis of Variance</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>Behavioral Sciences</subject><subject>Biological Techniques</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cycloheximide - pharmacology</subject><subject>Disease Models, Animal</subject><subject>Electric Stimulation - methods</subject><subject>Exploratory Behavior - physiology</subject><subject>Fragile X Mental Retardation Protein</subject><subject>Fragile X syndrome</subject><subject>Fragile X Syndrome - genetics</subject><subject>Fragile X Syndrome - metabolism</subject><subject>Fragile X Syndrome - pathology</subject><subject>Fragile X Syndrome - physiopathology</subject><subject>Gene Expression Regulation - genetics</subject><subject>Gene Expression Regulation - physiology</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Hippocampus - pathology</subject><subject>Hippocampus - physiopathology</subject><subject>Homer Scaffolding Proteins</subject><subject>Immunoprecipitation</subject><subject>In Vitro Techniques</subject><subject>Long-Term Potentiation - drug effects</subject><subject>Long-Term Potentiation - genetics</subject><subject>Methoxyhydroxyphenylglycol - analogs & derivatives</subject><subject>Methoxyhydroxyphenylglycol - pharmacology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Mutation</subject><subject>Nerve Net - drug effects</subject><subject>Nerve Net - physiology</subject><subject>Neurobiology</subject><subject>Neurosciences</subject><subject>Neurotransmitter receptors</subject><subject>Patch-Clamp Techniques</subject><subject>Peptides - pharmacology</subject><subject>Physics</subject><subject>Physiological aspects</subject><subject>Protein Synthesis Inhibitors - pharmacology</subject><subject>Rats</subject><subject>Rats, Long-Evans</subject><subject>Receptor, Metabotropic Glutamate 5</subject><subject>Receptors, Metabotropic Glutamate - chemistry</subject><subject>Receptors, Metabotropic Glutamate - metabolism</subject><subject>Risk factors</subject><subject>Serine - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - genetics</subject><subject>TOR Serine-Threonine Kinases - 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Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome</title><author>Ronesi, Jennifer A ; Collins, Katie A ; Hays, Seth A ; Tsai, Nien-Pei ; Guo, Weirui ; Birnbaum, Shari G ; Hu, Jia-Hua ; Worley, Paul F ; Gibson, Jay R ; Huber, Kimberly M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-ab766133226988324c4f09ce0cdde58f4266181451c6136a65f421a37b15ec003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>631/378/1689</topic><topic>631/378/340</topic><topic>Analysis of Variance</topic><topic>Animal Genetics and Genomics</topic><topic>Animals</topic><topic>Behavioral Sciences</topic><topic>Biological Techniques</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cycloheximide - pharmacology</topic><topic>Disease Models, Animal</topic><topic>Electric Stimulation - methods</topic><topic>Exploratory Behavior - physiology</topic><topic>Fragile X Mental Retardation Protein</topic><topic>Fragile X syndrome</topic><topic>Fragile X Syndrome - genetics</topic><topic>Fragile X Syndrome - metabolism</topic><topic>Fragile X Syndrome - pathology</topic><topic>Fragile X Syndrome - physiopathology</topic><topic>Gene Expression Regulation - genetics</topic><topic>Gene Expression Regulation - physiology</topic><topic>Gene mutations</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Hippocampus - pathology</topic><topic>Hippocampus - physiopathology</topic><topic>Homer Scaffolding Proteins</topic><topic>Immunoprecipitation</topic><topic>In Vitro Techniques</topic><topic>Long-Term Potentiation - drug effects</topic><topic>Long-Term Potentiation - genetics</topic><topic>Methoxyhydroxyphenylglycol - analogs & derivatives</topic><topic>Methoxyhydroxyphenylglycol - pharmacology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Mutation</topic><topic>Nerve Net - drug effects</topic><topic>Nerve Net - physiology</topic><topic>Neurobiology</topic><topic>Neurosciences</topic><topic>Neurotransmitter receptors</topic><topic>Patch-Clamp Techniques</topic><topic>Peptides - pharmacology</topic><topic>Physics</topic><topic>Physiological aspects</topic><topic>Protein Synthesis Inhibitors - pharmacology</topic><topic>Rats</topic><topic>Rats, Long-Evans</topic><topic>Receptor, Metabotropic Glutamate 5</topic><topic>Receptors, Metabotropic Glutamate - chemistry</topic><topic>Receptors, Metabotropic Glutamate - metabolism</topic><topic>Risk factors</topic><topic>Serine - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - genetics</topic><topic>TOR Serine-Threonine Kinases - 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mediate abnormal mGluR5 function in a mouse model of fragile X syndrome</atitle><jtitle>Nature neuroscience</jtitle><stitle>Nat Neurosci</stitle><addtitle>Nat Neurosci</addtitle><date>2012-03-01</date><risdate>2012</risdate><volume>15</volume><issue>3</issue><spage>431</spage><epage>440</epage><pages>431-440</pages><issn>1097-6256</issn><eissn>1546-1726</eissn><coden>NANEFN</coden><abstract>This study shows that the interaction between metabotropic glutamate receptor 5 (mGluR5) and a specific form of the scaffolding protein Homer contributes to the behavioral and physiological defects in the mouse model of fragile X syndrome.
Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model,
Fmr1
knockout (
Fmr1
−/
y
). In
Fmr1
−/
y
mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5–long Homer scaffolds and corrected several phenotypes in
Fmr1
−/
y
mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many
Fmr1
−/
y
phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of
Fmr1
. Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>22267161</pmid><doi>10.1038/nn.3033</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1097-6256 |
| ispartof | Nature neuroscience, 2012-03, Vol.15 (3), p.431-440 |
| issn | 1097-6256 1546-1726 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1028027665 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 631/378/1689 631/378/340 Analysis of Variance Animal Genetics and Genomics Animals Behavioral Sciences Biological Techniques Biomedical and Life Sciences Biomedicine Carrier Proteins - genetics Carrier Proteins - metabolism Cycloheximide - pharmacology Disease Models, Animal Electric Stimulation - methods Exploratory Behavior - physiology Fragile X Mental Retardation Protein Fragile X syndrome Fragile X Syndrome - genetics Fragile X Syndrome - metabolism Fragile X Syndrome - pathology Fragile X Syndrome - physiopathology Gene Expression Regulation - genetics Gene Expression Regulation - physiology Gene mutations Genetic aspects Health aspects Hippocampus - pathology Hippocampus - physiopathology Homer Scaffolding Proteins Immunoprecipitation In Vitro Techniques Long-Term Potentiation - drug effects Long-Term Potentiation - genetics Methoxyhydroxyphenylglycol - analogs & derivatives Methoxyhydroxyphenylglycol - pharmacology Mice Mice, Inbred C57BL Mice, Transgenic Mutation Nerve Net - drug effects Nerve Net - physiology Neurobiology Neurosciences Neurotransmitter receptors Patch-Clamp Techniques Peptides - pharmacology Physics Physiological aspects Protein Synthesis Inhibitors - pharmacology Rats Rats, Long-Evans Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate - chemistry Receptors, Metabotropic Glutamate - metabolism Risk factors Serine - metabolism Signal Transduction - drug effects Signal Transduction - genetics TOR Serine-Threonine Kinases - metabolism |
| title | Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T11%3A01%3A54IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Disrupted%20Homer%20scaffolds%20mediate%20abnormal%20mGluR5%20function%20in%20a%20mouse%20model%20of%20fragile%20X%20syndrome&rft.jtitle=Nature%20neuroscience&rft.au=Ronesi,%20Jennifer%20A&rft.date=2012-03-01&rft.volume=15&rft.issue=3&rft.spage=431&rft.epage=440&rft.pages=431-440&rft.issn=1097-6256&rft.eissn=1546-1726&rft.coden=NANEFN&rft_id=info:doi/10.1038/nn.3033&rft_dat=%3Cgale_proqu%3EA282325761%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1039470765&rft_id=info:pmid/22267161&rft_galeid=A282325761&rfr_iscdi=true |