A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment
Objective Early onset epileptic encephalopathy with suppression‐burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage‐dependent potassium channel subunit...
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| Veröffentlicht in: | Epilepsia (Copenhagen) 2020-05, Vol.61 (5), p.868-878 |
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| creator | Milh, Mathieu Roubertoux, Pierre Biba, Najoua Chavany, Julie Spiga Ghata, Adeline Fulachier, Camille Collins, Stephan Christopher Wagner, Christel Roux, Jean‐Christophe Yalcin, Binnaz Félix, Marie‐Solenne Molinari, Florence Lenck‐Santini, Pierre‐Pascal Villard, Laurent |
| description | Objective
Early onset epileptic encephalopathy with suppression‐burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage‐dependent potassium channel subunit, leading to so‐called KCNQ2‐related epileptic encephalopathy (KCNQ2‐REE). To study the pathophysiology of KCNQ2‐REE in detail and to provide a relevant preclinical model, we generated and described a knock‐in mouse model carrying the recurrent p.(Thr274Met) variant.
Methods
We introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre‐deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. We studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomical studies at different time points, and multiple behavioral tests.
Results
The Kcnq2Thr274Met/+ mice are viable and display generalized spontaneous seizures first observed between postnatal day 20 (P20) and P30. In vivo EEG recordings show that the paroxysmal events observed macroscopically are epileptic seizures. The brain of the Kcnq2Thr274Met/+ animals does not display major structural defects, similar to humans, and their body weight is normal. Kcnq2Thr274Met/+ mice have a reduced life span, with a peak of unexpected death occurring for 25% of the animals by 3 months of age. Epileptic seizures were generally not observed when animals grew older. Behavioral characterization reveals important deficits in spatial learning and memory in adults but no gross abnormality during early neurosensory development.
Significance
Taken together, our results indicate that we have generated a relevant model to study the pathophysiology of KCNQ2‐related epileptic encephalopathy and perform preclinical research for that devastating and currently intractable disease. |
| doi_str_mv | 10.1111/epi.16494 |
| format | Article |
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Early onset epileptic encephalopathy with suppression‐burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage‐dependent potassium channel subunit, leading to so‐called KCNQ2‐related epileptic encephalopathy (KCNQ2‐REE). To study the pathophysiology of KCNQ2‐REE in detail and to provide a relevant preclinical model, we generated and described a knock‐in mouse model carrying the recurrent p.(Thr274Met) variant.
Methods
We introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre‐deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. We studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomical studies at different time points, and multiple behavioral tests.
Results
The Kcnq2Thr274Met/+ mice are viable and display generalized spontaneous seizures first observed between postnatal day 20 (P20) and P30. In vivo EEG recordings show that the paroxysmal events observed macroscopically are epileptic seizures. The brain of the Kcnq2Thr274Met/+ animals does not display major structural defects, similar to humans, and their body weight is normal. Kcnq2Thr274Met/+ mice have a reduced life span, with a peak of unexpected death occurring for 25% of the animals by 3 months of age. Epileptic seizures were generally not observed when animals grew older. Behavioral characterization reveals important deficits in spatial learning and memory in adults but no gross abnormality during early neurosensory development.
Significance
Taken together, our results indicate that we have generated a relevant model to study the pathophysiology of KCNQ2‐related epileptic encephalopathy and perform preclinical research for that devastating and currently intractable disease.</description><identifier>ISSN: 0013-9580</identifier><identifier>EISSN: 1528-1167</identifier><identifier>DOI: 10.1111/epi.16494</identifier><identifier>PMID: 32239694</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Anatomy ; Blastocysts ; Body weight ; Brain architecture ; Cognitive ability ; Convulsions & seizures ; EEG ; Embryo cells ; Encephalopathy ; Epilepsy ; epileptic encephalopathy ; Full Length Original Research ; Genetics ; Homologous recombination ; KCNQ2 ; KCNQ2 protein ; Life Sciences ; Life span ; mouse model ; Neurobiology ; Neurons and Cognition ; Pathophysiology ; Phenotypes ; Potassium channels (voltage-gated) ; Pseudopregnancy ; Seizures ; Spatial discrimination learning ; Spatial memory ; Stem cell transplantation ; Stem cells</subject><ispartof>Epilepsia (Copenhagen), 2020-05, Vol.61 (5), p.868-878</ispartof><rights>2020 The Authors. published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy</rights><rights>2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4804-150a074af89262ddd214a143fae14473d8a87e00a184b5e98907084103ea635e3</citedby><cites>FETCH-LOGICAL-c4804-150a074af89262ddd214a143fae14473d8a87e00a184b5e98907084103ea635e3</cites><orcidid>0000-0001-9013-2725 ; 0000-0001-9925-9220 ; 0000-0002-2454-8543 ; 0000-0001-5111-7215 ; 0000-0002-9721-8844 ; 0000-0001-6657-5008 ; 0000-0002-1924-6807</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fepi.16494$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fepi.16494$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32239694$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-02551507$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Milh, Mathieu</creatorcontrib><creatorcontrib>Roubertoux, Pierre</creatorcontrib><creatorcontrib>Biba, Najoua</creatorcontrib><creatorcontrib>Chavany, Julie</creatorcontrib><creatorcontrib>Spiga Ghata, Adeline</creatorcontrib><creatorcontrib>Fulachier, Camille</creatorcontrib><creatorcontrib>Collins, Stephan Christopher</creatorcontrib><creatorcontrib>Wagner, Christel</creatorcontrib><creatorcontrib>Roux, Jean‐Christophe</creatorcontrib><creatorcontrib>Yalcin, Binnaz</creatorcontrib><creatorcontrib>Félix, Marie‐Solenne</creatorcontrib><creatorcontrib>Molinari, Florence</creatorcontrib><creatorcontrib>Lenck‐Santini, Pierre‐Pascal</creatorcontrib><creatorcontrib>Villard, Laurent</creatorcontrib><title>A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment</title><title>Epilepsia (Copenhagen)</title><addtitle>Epilepsia</addtitle><description>Objective
Early onset epileptic encephalopathy with suppression‐burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage‐dependent potassium channel subunit, leading to so‐called KCNQ2‐related epileptic encephalopathy (KCNQ2‐REE). To study the pathophysiology of KCNQ2‐REE in detail and to provide a relevant preclinical model, we generated and described a knock‐in mouse model carrying the recurrent p.(Thr274Met) variant.
Methods
We introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre‐deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. We studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomical studies at different time points, and multiple behavioral tests.
Results
The Kcnq2Thr274Met/+ mice are viable and display generalized spontaneous seizures first observed between postnatal day 20 (P20) and P30. In vivo EEG recordings show that the paroxysmal events observed macroscopically are epileptic seizures. The brain of the Kcnq2Thr274Met/+ animals does not display major structural defects, similar to humans, and their body weight is normal. Kcnq2Thr274Met/+ mice have a reduced life span, with a peak of unexpected death occurring for 25% of the animals by 3 months of age. Epileptic seizures were generally not observed when animals grew older. Behavioral characterization reveals important deficits in spatial learning and memory in adults but no gross abnormality during early neurosensory development.
Significance
Taken together, our results indicate that we have generated a relevant model to study the pathophysiology of KCNQ2‐related epileptic encephalopathy and perform preclinical research for that devastating and currently intractable disease.</description><subject>Anatomy</subject><subject>Blastocysts</subject><subject>Body weight</subject><subject>Brain architecture</subject><subject>Cognitive ability</subject><subject>Convulsions & seizures</subject><subject>EEG</subject><subject>Embryo cells</subject><subject>Encephalopathy</subject><subject>Epilepsy</subject><subject>epileptic encephalopathy</subject><subject>Full Length Original Research</subject><subject>Genetics</subject><subject>Homologous recombination</subject><subject>KCNQ2</subject><subject>KCNQ2 protein</subject><subject>Life Sciences</subject><subject>Life span</subject><subject>mouse model</subject><subject>Neurobiology</subject><subject>Neurons and Cognition</subject><subject>Pathophysiology</subject><subject>Phenotypes</subject><subject>Potassium channels (voltage-gated)</subject><subject>Pseudopregnancy</subject><subject>Seizures</subject><subject>Spatial discrimination learning</subject><subject>Spatial memory</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><issn>0013-9580</issn><issn>1528-1167</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNp1kk1vEzEQhi0EoiFw4A8gS1xAIu34Y9feC1IUtbQi4kOCs-XuThK3u_Zib4LSU48c-Y38EgxbKqiED_Zhnnnf8cwQ8pTBIcvnCHt3yEpZyXtkwgquZ4yV6j6ZADAxqwoNB-RRShcAoEolHpIDwbmoykpOyLc5vfShvvxx_d152oVtwnw32NJViPTt4t1HnkMRWztgQ7NRi_3gaoq-xn5j29DbYbOnjUt9a_eJpj74wXrMQnSNHqNt3VXOTOiuthETtb6hdVh7N7gdUtf11sUO_fCYPFjZNuGTm3dKPp8cf1qczpbv35wt5stZLTXIGSvAgpJ2pSte8qZpOJOWSbGyyKRUotFWKwSwTMvzAitdgQItGQi0pShQTMnrUbffnnfY1Nk612j66Dob9yZYZ_6NeLcx67AzSjDFs86UvBoFNnfSTudL43zC2BngRZErVTuW8Rc3fjF82WIaTOdSjW07NslwoQsFFRNlRp_fQS_CNvrcDcMlaFUxKESmXo5UHUNKEVe3RTAwv9bB5CmZ3-uQ2Wd_f_aW_DP_DByNwNc82P3_lczxh7NR8idLJMKc</recordid><startdate>202005</startdate><enddate>202005</enddate><creator>Milh, Mathieu</creator><creator>Roubertoux, Pierre</creator><creator>Biba, Najoua</creator><creator>Chavany, Julie</creator><creator>Spiga Ghata, Adeline</creator><creator>Fulachier, Camille</creator><creator>Collins, Stephan Christopher</creator><creator>Wagner, Christel</creator><creator>Roux, Jean‐Christophe</creator><creator>Yalcin, Binnaz</creator><creator>Félix, Marie‐Solenne</creator><creator>Molinari, Florence</creator><creator>Lenck‐Santini, Pierre‐Pascal</creator><creator>Villard, Laurent</creator><general>Wiley Subscription Services, Inc</general><general>Wiley</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9013-2725</orcidid><orcidid>https://orcid.org/0000-0001-9925-9220</orcidid><orcidid>https://orcid.org/0000-0002-2454-8543</orcidid><orcidid>https://orcid.org/0000-0001-5111-7215</orcidid><orcidid>https://orcid.org/0000-0002-9721-8844</orcidid><orcidid>https://orcid.org/0000-0001-6657-5008</orcidid><orcidid>https://orcid.org/0000-0002-1924-6807</orcidid></search><sort><creationdate>202005</creationdate><title>A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment</title><author>Milh, Mathieu ; Roubertoux, Pierre ; Biba, Najoua ; Chavany, Julie ; Spiga Ghata, Adeline ; Fulachier, Camille ; Collins, Stephan Christopher ; Wagner, Christel ; Roux, Jean‐Christophe ; Yalcin, Binnaz ; Félix, Marie‐Solenne ; Molinari, Florence ; Lenck‐Santini, Pierre‐Pascal ; Villard, Laurent</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4804-150a074af89262ddd214a143fae14473d8a87e00a184b5e98907084103ea635e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Anatomy</topic><topic>Blastocysts</topic><topic>Body weight</topic><topic>Brain architecture</topic><topic>Cognitive ability</topic><topic>Convulsions & seizures</topic><topic>EEG</topic><topic>Embryo cells</topic><topic>Encephalopathy</topic><topic>Epilepsy</topic><topic>epileptic encephalopathy</topic><topic>Full Length Original Research</topic><topic>Genetics</topic><topic>Homologous recombination</topic><topic>KCNQ2</topic><topic>KCNQ2 protein</topic><topic>Life Sciences</topic><topic>Life span</topic><topic>mouse model</topic><topic>Neurobiology</topic><topic>Neurons and Cognition</topic><topic>Pathophysiology</topic><topic>Phenotypes</topic><topic>Potassium channels (voltage-gated)</topic><topic>Pseudopregnancy</topic><topic>Seizures</topic><topic>Spatial discrimination learning</topic><topic>Spatial memory</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Milh, Mathieu</creatorcontrib><creatorcontrib>Roubertoux, Pierre</creatorcontrib><creatorcontrib>Biba, Najoua</creatorcontrib><creatorcontrib>Chavany, Julie</creatorcontrib><creatorcontrib>Spiga Ghata, Adeline</creatorcontrib><creatorcontrib>Fulachier, Camille</creatorcontrib><creatorcontrib>Collins, Stephan Christopher</creatorcontrib><creatorcontrib>Wagner, Christel</creatorcontrib><creatorcontrib>Roux, Jean‐Christophe</creatorcontrib><creatorcontrib>Yalcin, Binnaz</creatorcontrib><creatorcontrib>Félix, Marie‐Solenne</creatorcontrib><creatorcontrib>Molinari, Florence</creatorcontrib><creatorcontrib>Lenck‐Santini, Pierre‐Pascal</creatorcontrib><creatorcontrib>Villard, Laurent</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Epilepsia (Copenhagen)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Milh, Mathieu</au><au>Roubertoux, Pierre</au><au>Biba, Najoua</au><au>Chavany, Julie</au><au>Spiga Ghata, Adeline</au><au>Fulachier, Camille</au><au>Collins, Stephan Christopher</au><au>Wagner, Christel</au><au>Roux, Jean‐Christophe</au><au>Yalcin, Binnaz</au><au>Félix, Marie‐Solenne</au><au>Molinari, Florence</au><au>Lenck‐Santini, Pierre‐Pascal</au><au>Villard, Laurent</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment</atitle><jtitle>Epilepsia (Copenhagen)</jtitle><addtitle>Epilepsia</addtitle><date>2020-05</date><risdate>2020</risdate><volume>61</volume><issue>5</issue><spage>868</spage><epage>878</epage><pages>868-878</pages><issn>0013-9580</issn><eissn>1528-1167</eissn><abstract>Objective
Early onset epileptic encephalopathy with suppression‐burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage‐dependent potassium channel subunit, leading to so‐called KCNQ2‐related epileptic encephalopathy (KCNQ2‐REE). To study the pathophysiology of KCNQ2‐REE in detail and to provide a relevant preclinical model, we generated and described a knock‐in mouse model carrying the recurrent p.(Thr274Met) variant.
Methods
We introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre‐deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. We studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomical studies at different time points, and multiple behavioral tests.
Results
The Kcnq2Thr274Met/+ mice are viable and display generalized spontaneous seizures first observed between postnatal day 20 (P20) and P30. In vivo EEG recordings show that the paroxysmal events observed macroscopically are epileptic seizures. The brain of the Kcnq2Thr274Met/+ animals does not display major structural defects, similar to humans, and their body weight is normal. Kcnq2Thr274Met/+ mice have a reduced life span, with a peak of unexpected death occurring for 25% of the animals by 3 months of age. Epileptic seizures were generally not observed when animals grew older. Behavioral characterization reveals important deficits in spatial learning and memory in adults but no gross abnormality during early neurosensory development.
Significance
Taken together, our results indicate that we have generated a relevant model to study the pathophysiology of KCNQ2‐related epileptic encephalopathy and perform preclinical research for that devastating and currently intractable disease.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>32239694</pmid><doi>10.1111/epi.16494</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-9013-2725</orcidid><orcidid>https://orcid.org/0000-0001-9925-9220</orcidid><orcidid>https://orcid.org/0000-0002-2454-8543</orcidid><orcidid>https://orcid.org/0000-0001-5111-7215</orcidid><orcidid>https://orcid.org/0000-0002-9721-8844</orcidid><orcidid>https://orcid.org/0000-0001-6657-5008</orcidid><orcidid>https://orcid.org/0000-0002-1924-6807</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Epilepsia (Copenhagen), 2020-05, Vol.61 (5), p.868-878 |
| issn | 0013-9580 1528-1167 |
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| source | Wiley Online Library Journals Frontfile Complete; Wiley Online Library Free Content; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Anatomy Blastocysts Body weight Brain architecture Cognitive ability Convulsions & seizures EEG Embryo cells Encephalopathy Epilepsy epileptic encephalopathy Full Length Original Research Genetics Homologous recombination KCNQ2 KCNQ2 protein Life Sciences Life span mouse model Neurobiology Neurons and Cognition Pathophysiology Phenotypes Potassium channels (voltage-gated) Pseudopregnancy Seizures Spatial discrimination learning Spatial memory Stem cell transplantation Stem cells |
| title | A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment |
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