Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model
Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless het...
Gespeichert in:
| Veröffentlicht in: | Nature communications 2014-08, Vol.5 (1), p.4563 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 1 |
| container_start_page | 4563 |
| container_title | Nature communications |
| container_volume | 5 |
| creator | Lozovaya, N. Gataullina, S. Tsintsadze, T. Tsintsadze, V. Pallesi-Pocachard, E. Minlebaev, M. Goriounova, N. A. Buhler, E. Watrin, F. Shityakov, S. Becker, A. J. Bordey, A. Milh, M. Scavarda, D. Bulteau, C. Dorfmuller, G. Delalande, O. Represa, A. Cardoso, C. Dulac, O. Ben-Ari, Y. Burnashev, N. |
| description | Tuberous sclerosis complex (TSC), caused by dominant mutations in either
TSC1
or
TSC2
tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote
Tsc1
+/−
mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life ( |
| doi_str_mv | 10.1038/ncomms5563 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4143949</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3389748971</sourcerecordid><originalsourceid>FETCH-LOGICAL-p227t-71bb12984619f8e182780d863803403b94f6641f63127e290fc6e93dc6bcf2db3</originalsourceid><addsrcrecordid>eNpVkU1LxDAQhoMguqgXf4AEPMpqvpqmF0EWXYVFD-o5tOl0zdI2MWkX99-bxa91LjOT9-WZJIPQKSWXlHB11RvXdTHLJN9DE0YEndKc8UN0EuOKpOAFVUIcoEOWEUVJlk-Qf4YWzGDXgOPofYAYreuxazB8mG2ThHk7PrJZOviVUzYjRAxlaDcYvG3Bxw22PS7xMFYQ3BhxNG0qoo24G4PtAXeuhvYY7TdlG-HkOx-h17vbl9n9dPE0f5jdLKaesXyY5rSqKCuUkLRoFFDFckVqJbkiXBBeFaKRUtBGcspyYAVpjISC10ZWpmF1xY_Q9RfXj1UHtYF-CGWrfbBdGTbalVb_V3r7ppdurQUVvBBFApx_A4J7T48d9MqNoU931jTLCGVMsiy5znbH_PJ_fjgZLr4MMUn9EsIOhujt2vTf2vgnQmONjA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1550122625</pqid></control><display><type>article</type><title>Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model</title><source>MEDLINE</source><source>Springer Nature OA Free Journals</source><source>Nature Free</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Lozovaya, N. ; Gataullina, S. ; Tsintsadze, T. ; Tsintsadze, V. ; Pallesi-Pocachard, E. ; Minlebaev, M. ; Goriounova, N. A. ; Buhler, E. ; Watrin, F. ; Shityakov, S. ; Becker, A. J. ; Bordey, A. ; Milh, M. ; Scavarda, D. ; Bulteau, C. ; Dorfmuller, G. ; Delalande, O. ; Represa, A. ; Cardoso, C. ; Dulac, O. ; Ben-Ari, Y. ; Burnashev, N.</creator><creatorcontrib>Lozovaya, N. ; Gataullina, S. ; Tsintsadze, T. ; Tsintsadze, V. ; Pallesi-Pocachard, E. ; Minlebaev, M. ; Goriounova, N. A. ; Buhler, E. ; Watrin, F. ; Shityakov, S. ; Becker, A. J. ; Bordey, A. ; Milh, M. ; Scavarda, D. ; Bulteau, C. ; Dorfmuller, G. ; Delalande, O. ; Represa, A. ; Cardoso, C. ; Dulac, O. ; Ben-Ari, Y. ; Burnashev, N.</creatorcontrib><description>Tuberous sclerosis complex (TSC), caused by dominant mutations in either
TSC1
or
TSC2
tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote
Tsc1
+/−
mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (<P19). Seizures are generated intracortically in the granular layer of the neocortex. Slow kinetics of aberrant GluN2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in
Tsc1
+/−
mice
in vivo
and
in vitro
. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients.
Tuberous sclerosis complex (TSC) is a rare genetic condition characterized by epileptic seizures that start in infancy. Here, the authors show that these seizures are modulated by GluN2C-containing NMDA receptors in the cortex of a mouse model of TSC, and that suppressing their activity attenuates seizures.</description><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms5563</identifier><identifier>PMID: 25081057</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/109 ; 13/44 ; 14/19 ; 14/34 ; 14/35 ; 38 ; 38/109 ; 38/22 ; 38/77 ; 38/90 ; 42 ; 631/208/2489/144 ; 631/378/1689 ; 631/378/1689/178 ; 64/110 ; 9/74 ; Action Potentials - drug effects ; Animals ; Anticonvulsants - pharmacology ; Disease Models, Animal ; Electroencephalography ; Epilepsy - drug therapy ; Epilepsy - genetics ; Epilepsy - metabolism ; Epilepsy - pathology ; Gene Expression Regulation ; Heterozygote ; Humanities and Social Sciences ; Humans ; Male ; Mice ; Mice, Transgenic ; Microtomy ; multidisciplinary ; Neocortex - drug effects ; Neocortex - metabolism ; Neocortex - pathology ; Patch-Clamp Techniques ; Pyrazoles - pharmacology ; Quinolones - pharmacology ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate - genetics ; Receptors, N-Methyl-D-Aspartate - metabolism ; Science ; Science (multidisciplinary) ; Signal Transduction ; Tissue Culture Techniques ; TOR Serine-Threonine Kinases - genetics ; TOR Serine-Threonine Kinases - metabolism ; Tuberous Sclerosis - drug therapy ; Tuberous Sclerosis - genetics ; Tuberous Sclerosis - metabolism ; Tuberous Sclerosis - pathology ; Tumor Suppressor Proteins - deficiency ; Tumor Suppressor Proteins - genetics</subject><ispartof>Nature communications, 2014-08, Vol.5 (1), p.4563</ispartof><rights>The Author(s) 2014</rights><rights>Copyright Nature Publishing Group Aug 2014</rights><rights>Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143949/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143949/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25081057$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lozovaya, N.</creatorcontrib><creatorcontrib>Gataullina, S.</creatorcontrib><creatorcontrib>Tsintsadze, T.</creatorcontrib><creatorcontrib>Tsintsadze, V.</creatorcontrib><creatorcontrib>Pallesi-Pocachard, E.</creatorcontrib><creatorcontrib>Minlebaev, M.</creatorcontrib><creatorcontrib>Goriounova, N. A.</creatorcontrib><creatorcontrib>Buhler, E.</creatorcontrib><creatorcontrib>Watrin, F.</creatorcontrib><creatorcontrib>Shityakov, S.</creatorcontrib><creatorcontrib>Becker, A. J.</creatorcontrib><creatorcontrib>Bordey, A.</creatorcontrib><creatorcontrib>Milh, M.</creatorcontrib><creatorcontrib>Scavarda, D.</creatorcontrib><creatorcontrib>Bulteau, C.</creatorcontrib><creatorcontrib>Dorfmuller, G.</creatorcontrib><creatorcontrib>Delalande, O.</creatorcontrib><creatorcontrib>Represa, A.</creatorcontrib><creatorcontrib>Cardoso, C.</creatorcontrib><creatorcontrib>Dulac, O.</creatorcontrib><creatorcontrib>Ben-Ari, Y.</creatorcontrib><creatorcontrib>Burnashev, N.</creatorcontrib><title>Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>Tuberous sclerosis complex (TSC), caused by dominant mutations in either
TSC1
or
TSC2
tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote
Tsc1
+/−
mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (<P19). Seizures are generated intracortically in the granular layer of the neocortex. Slow kinetics of aberrant GluN2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in
Tsc1
+/−
mice
in vivo
and
in vitro
. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients.
Tuberous sclerosis complex (TSC) is a rare genetic condition characterized by epileptic seizures that start in infancy. Here, the authors show that these seizures are modulated by GluN2C-containing NMDA receptors in the cortex of a mouse model of TSC, and that suppressing their activity attenuates seizures.</description><subject>13</subject><subject>13/1</subject><subject>13/109</subject><subject>13/44</subject><subject>14/19</subject><subject>14/34</subject><subject>14/35</subject><subject>38</subject><subject>38/109</subject><subject>38/22</subject><subject>38/77</subject><subject>38/90</subject><subject>42</subject><subject>631/208/2489/144</subject><subject>631/378/1689</subject><subject>631/378/1689/178</subject><subject>64/110</subject><subject>9/74</subject><subject>Action Potentials - drug effects</subject><subject>Animals</subject><subject>Anticonvulsants - pharmacology</subject><subject>Disease Models, Animal</subject><subject>Electroencephalography</subject><subject>Epilepsy - drug therapy</subject><subject>Epilepsy - genetics</subject><subject>Epilepsy - metabolism</subject><subject>Epilepsy - pathology</subject><subject>Gene Expression Regulation</subject><subject>Heterozygote</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microtomy</subject><subject>multidisciplinary</subject><subject>Neocortex - drug effects</subject><subject>Neocortex - metabolism</subject><subject>Neocortex - pathology</subject><subject>Patch-Clamp Techniques</subject><subject>Pyrazoles - pharmacology</subject><subject>Quinolones - pharmacology</subject><subject>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</subject><subject>Receptors, N-Methyl-D-Aspartate - genetics</subject><subject>Receptors, N-Methyl-D-Aspartate - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal Transduction</subject><subject>Tissue Culture Techniques</subject><subject>TOR Serine-Threonine Kinases - genetics</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Tuberous Sclerosis - drug therapy</subject><subject>Tuberous Sclerosis - genetics</subject><subject>Tuberous Sclerosis - metabolism</subject><subject>Tuberous Sclerosis - pathology</subject><subject>Tumor Suppressor Proteins - deficiency</subject><subject>Tumor Suppressor Proteins - genetics</subject><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpVkU1LxDAQhoMguqgXf4AEPMpqvpqmF0EWXYVFD-o5tOl0zdI2MWkX99-bxa91LjOT9-WZJIPQKSWXlHB11RvXdTHLJN9DE0YEndKc8UN0EuOKpOAFVUIcoEOWEUVJlk-Qf4YWzGDXgOPofYAYreuxazB8mG2ThHk7PrJZOviVUzYjRAxlaDcYvG3Bxw22PS7xMFYQ3BhxNG0qoo24G4PtAXeuhvYY7TdlG-HkOx-h17vbl9n9dPE0f5jdLKaesXyY5rSqKCuUkLRoFFDFckVqJbkiXBBeFaKRUtBGcspyYAVpjISC10ZWpmF1xY_Q9RfXj1UHtYF-CGWrfbBdGTbalVb_V3r7ppdurQUVvBBFApx_A4J7T48d9MqNoU931jTLCGVMsiy5znbH_PJ_fjgZLr4MMUn9EsIOhujt2vTf2vgnQmONjA</recordid><startdate>20140801</startdate><enddate>20140801</enddate><creator>Lozovaya, N.</creator><creator>Gataullina, S.</creator><creator>Tsintsadze, T.</creator><creator>Tsintsadze, V.</creator><creator>Pallesi-Pocachard, E.</creator><creator>Minlebaev, M.</creator><creator>Goriounova, N. A.</creator><creator>Buhler, E.</creator><creator>Watrin, F.</creator><creator>Shityakov, S.</creator><creator>Becker, A. J.</creator><creator>Bordey, A.</creator><creator>Milh, M.</creator><creator>Scavarda, D.</creator><creator>Bulteau, C.</creator><creator>Dorfmuller, G.</creator><creator>Delalande, O.</creator><creator>Represa, A.</creator><creator>Cardoso, C.</creator><creator>Dulac, O.</creator><creator>Ben-Ari, Y.</creator><creator>Burnashev, N.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><general>Nature Pub. Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>SOI</scope><scope>5PM</scope></search><sort><creationdate>20140801</creationdate><title>Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model</title><author>Lozovaya, N. ; Gataullina, S. ; Tsintsadze, T. ; Tsintsadze, V. ; Pallesi-Pocachard, E. ; Minlebaev, M. ; Goriounova, N. A. ; Buhler, E. ; Watrin, F. ; Shityakov, S. ; Becker, A. J. ; Bordey, A. ; Milh, M. ; Scavarda, D. ; Bulteau, C. ; Dorfmuller, G. ; Delalande, O. ; Represa, A. ; Cardoso, C. ; Dulac, O. ; Ben-Ari, Y. ; Burnashev, N.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p227t-71bb12984619f8e182780d863803403b94f6641f63127e290fc6e93dc6bcf2db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>13</topic><topic>13/1</topic><topic>13/109</topic><topic>13/44</topic><topic>14/19</topic><topic>14/34</topic><topic>14/35</topic><topic>38</topic><topic>38/109</topic><topic>38/22</topic><topic>38/77</topic><topic>38/90</topic><topic>42</topic><topic>631/208/2489/144</topic><topic>631/378/1689</topic><topic>631/378/1689/178</topic><topic>64/110</topic><topic>9/74</topic><topic>Action Potentials - drug effects</topic><topic>Animals</topic><topic>Anticonvulsants - pharmacology</topic><topic>Disease Models, Animal</topic><topic>Electroencephalography</topic><topic>Epilepsy - drug therapy</topic><topic>Epilepsy - genetics</topic><topic>Epilepsy - metabolism</topic><topic>Epilepsy - pathology</topic><topic>Gene Expression Regulation</topic><topic>Heterozygote</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Microtomy</topic><topic>multidisciplinary</topic><topic>Neocortex - drug effects</topic><topic>Neocortex - metabolism</topic><topic>Neocortex - pathology</topic><topic>Patch-Clamp Techniques</topic><topic>Pyrazoles - pharmacology</topic><topic>Quinolones - pharmacology</topic><topic>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</topic><topic>Receptors, N-Methyl-D-Aspartate - genetics</topic><topic>Receptors, N-Methyl-D-Aspartate - metabolism</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signal Transduction</topic><topic>Tissue Culture Techniques</topic><topic>TOR Serine-Threonine Kinases - genetics</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Tuberous Sclerosis - drug therapy</topic><topic>Tuberous Sclerosis - genetics</topic><topic>Tuberous Sclerosis - metabolism</topic><topic>Tuberous Sclerosis - pathology</topic><topic>Tumor Suppressor Proteins - deficiency</topic><topic>Tumor Suppressor Proteins - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lozovaya, N.</creatorcontrib><creatorcontrib>Gataullina, S.</creatorcontrib><creatorcontrib>Tsintsadze, T.</creatorcontrib><creatorcontrib>Tsintsadze, V.</creatorcontrib><creatorcontrib>Pallesi-Pocachard, E.</creatorcontrib><creatorcontrib>Minlebaev, M.</creatorcontrib><creatorcontrib>Goriounova, N. A.</creatorcontrib><creatorcontrib>Buhler, E.</creatorcontrib><creatorcontrib>Watrin, F.</creatorcontrib><creatorcontrib>Shityakov, S.</creatorcontrib><creatorcontrib>Becker, A. J.</creatorcontrib><creatorcontrib>Bordey, A.</creatorcontrib><creatorcontrib>Milh, M.</creatorcontrib><creatorcontrib>Scavarda, D.</creatorcontrib><creatorcontrib>Bulteau, C.</creatorcontrib><creatorcontrib>Dorfmuller, G.</creatorcontrib><creatorcontrib>Delalande, O.</creatorcontrib><creatorcontrib>Represa, A.</creatorcontrib><creatorcontrib>Cardoso, C.</creatorcontrib><creatorcontrib>Dulac, O.</creatorcontrib><creatorcontrib>Ben-Ari, Y.</creatorcontrib><creatorcontrib>Burnashev, N.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Environment Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>Environment Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lozovaya, N.</au><au>Gataullina, S.</au><au>Tsintsadze, T.</au><au>Tsintsadze, V.</au><au>Pallesi-Pocachard, E.</au><au>Minlebaev, M.</au><au>Goriounova, N. A.</au><au>Buhler, E.</au><au>Watrin, F.</au><au>Shityakov, S.</au><au>Becker, A. J.</au><au>Bordey, A.</au><au>Milh, M.</au><au>Scavarda, D.</au><au>Bulteau, C.</au><au>Dorfmuller, G.</au><au>Delalande, O.</au><au>Represa, A.</au><au>Cardoso, C.</au><au>Dulac, O.</au><au>Ben-Ari, Y.</au><au>Burnashev, N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2014-08-01</date><risdate>2014</risdate><volume>5</volume><issue>1</issue><spage>4563</spage><pages>4563-</pages><eissn>2041-1723</eissn><abstract>Tuberous sclerosis complex (TSC), caused by dominant mutations in either
TSC1
or
TSC2
tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote
Tsc1
+/−
mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (<P19). Seizures are generated intracortically in the granular layer of the neocortex. Slow kinetics of aberrant GluN2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in
Tsc1
+/−
mice
in vivo
and
in vitro
. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients.
Tuberous sclerosis complex (TSC) is a rare genetic condition characterized by epileptic seizures that start in infancy. Here, the authors show that these seizures are modulated by GluN2C-containing NMDA receptors in the cortex of a mouse model of TSC, and that suppressing their activity attenuates seizures.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25081057</pmid><doi>10.1038/ncomms5563</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | EISSN: 2041-1723 |
| ispartof | Nature communications, 2014-08, Vol.5 (1), p.4563 |
| issn | 2041-1723 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4143949 |
| source | MEDLINE; Springer Nature OA Free Journals; Nature Free; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | 13 13/1 13/109 13/44 14/19 14/34 14/35 38 38/109 38/22 38/77 38/90 42 631/208/2489/144 631/378/1689 631/378/1689/178 64/110 9/74 Action Potentials - drug effects Animals Anticonvulsants - pharmacology Disease Models, Animal Electroencephalography Epilepsy - drug therapy Epilepsy - genetics Epilepsy - metabolism Epilepsy - pathology Gene Expression Regulation Heterozygote Humanities and Social Sciences Humans Male Mice Mice, Transgenic Microtomy multidisciplinary Neocortex - drug effects Neocortex - metabolism Neocortex - pathology Patch-Clamp Techniques Pyrazoles - pharmacology Quinolones - pharmacology Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism Science Science (multidisciplinary) Signal Transduction Tissue Culture Techniques TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism Tuberous Sclerosis - drug therapy Tuberous Sclerosis - genetics Tuberous Sclerosis - metabolism Tuberous Sclerosis - pathology Tumor Suppressor Proteins - deficiency Tumor Suppressor Proteins - genetics |
| title | Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T11%3A54%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Selective%20suppression%20of%20excessive%20GluN2C%20expression%20rescues%20early%20epilepsy%20in%20a%20tuberous%20sclerosis%20murine%20model&rft.jtitle=Nature%20communications&rft.au=Lozovaya,%20N.&rft.date=2014-08-01&rft.volume=5&rft.issue=1&rft.spage=4563&rft.pages=4563-&rft.eissn=2041-1723&rft_id=info:doi/10.1038/ncomms5563&rft_dat=%3Cproquest_pubme%3E3389748971%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1550122625&rft_id=info:pmid/25081057&rfr_iscdi=true |