Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory
Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors i...
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| creator | Okuda, Kosuke Takao, Keizo Watanabe, Aya Miyakawa, Tsuyoshi Mizuguchi, Masashi Tanaka, Teruyuki |
| description | Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder. |
| doi_str_mv | 10.1371/journal.pone.0196587 |
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Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0196587</identifier><identifier>PMID: 29702698</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anxiety ; Behavior ; Biology and Life Sciences ; Brain-derived neurotrophic factor ; Cell division ; Cognition ; Conditioning ; Cyclin-dependent kinase ; Cyclin-dependent kinases ; Dendritic branching ; Dendritic spines ; Developmental disabilities ; Emotional behavior ; Experiments ; Fear ; Fear conditioning ; Freezing ; Gait ; Gene mutation ; Genetic aspects ; Glutamic acid receptors (ionotropic) ; Hippocampus ; Inhibition (psychology) ; Kinases ; Laboratories ; Localization ; Medicine ; Medicine and Health Sciences ; Mice ; Morphometry ; Mutation ; N-Methyl-D-aspartic acid receptors ; Neurodevelopmental disorders ; Physiological aspects ; Physiology ; Protein kinases ; Proteins ; Pyramidal cells ; Receptors ; Research and Analysis Methods ; Retention ; Risk factors ; Rodents ; Schizophrenia ; Social behavior ; Social interactions ; Spatial memory ; Spine ; Tonic immobility</subject><ispartof>PloS one, 2018-04, Vol.13 (4), p.e0196587-e0196587</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Okuda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Okuda et al 2018 Okuda et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-f7d2fd23f7a5c56ae391c1e2d4108998a9cb9dccbf90f726a1dde1f122a98cd63</citedby><cites>FETCH-LOGICAL-c758t-f7d2fd23f7a5c56ae391c1e2d4108998a9cb9dccbf90f726a1dde1f122a98cd63</cites><orcidid>0000-0003-2000-5354</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922552/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922552/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29702698$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kavushansky, Alexandra</contributor><creatorcontrib>Okuda, Kosuke</creatorcontrib><creatorcontrib>Takao, Keizo</creatorcontrib><creatorcontrib>Watanabe, Aya</creatorcontrib><creatorcontrib>Miyakawa, Tsuyoshi</creatorcontrib><creatorcontrib>Mizuguchi, Masashi</creatorcontrib><creatorcontrib>Tanaka, Teruyuki</creatorcontrib><title>Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. 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These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.</description><subject>Anxiety</subject><subject>Behavior</subject><subject>Biology and Life Sciences</subject><subject>Brain-derived neurotrophic factor</subject><subject>Cell division</subject><subject>Cognition</subject><subject>Conditioning</subject><subject>Cyclin-dependent kinase</subject><subject>Cyclin-dependent kinases</subject><subject>Dendritic branching</subject><subject>Dendritic spines</subject><subject>Developmental disabilities</subject><subject>Emotional behavior</subject><subject>Experiments</subject><subject>Fear</subject><subject>Fear 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one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Okuda, Kosuke</au><au>Takao, Keizo</au><au>Watanabe, Aya</au><au>Miyakawa, Tsuyoshi</au><au>Mizuguchi, Masashi</au><au>Tanaka, Teruyuki</au><au>Kavushansky, Alexandra</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-04-27</date><risdate>2018</risdate><volume>13</volume><issue>4</issue><spage>e0196587</spage><epage>e0196587</epage><pages>e0196587-e0196587</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29702698</pmid><doi>10.1371/journal.pone.0196587</doi><tpages>e0196587</tpages><orcidid>https://orcid.org/0000-0003-2000-5354</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_2031702583 |
| source | Open Access: PubMed Central; Directory of Open Access Journals; Public Library of Science website; Free E-Journal (出版社公開部分のみ）; Free Full-Text Journals in Chemistry |
| subjects | Anxiety Behavior Biology and Life Sciences Brain-derived neurotrophic factor Cell division Cognition Conditioning Cyclin-dependent kinase Cyclin-dependent kinases Dendritic branching Dendritic spines Developmental disabilities Emotional behavior Experiments Fear Fear conditioning Freezing Gait Gene mutation Genetic aspects Glutamic acid receptors (ionotropic) Hippocampus Inhibition (psychology) Kinases Laboratories Localization Medicine Medicine and Health Sciences Mice Morphometry Mutation N-Methyl-D-aspartic acid receptors Neurodevelopmental disorders Physiological aspects Physiology Protein kinases Proteins Pyramidal cells Receptors Research and Analysis Methods Retention Risk factors Rodents Schizophrenia Social behavior Social interactions Spatial memory Spine Tonic immobility |
| title | Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T06%3A26%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Comprehensive%20behavioral%20analysis%20of%20the%20Cdkl5%20knockout%20mice%20revealed%20significant%20enhancement%20in%20anxiety-%20and%20fear-related%20behaviors%20and%20impairment%20in%20both%20acquisition%20and%20long-term%20retention%20of%20spatial%20reference%20memory&rft.jtitle=PloS%20one&rft.au=Okuda,%20Kosuke&rft.date=2018-04-27&rft.volume=13&rft.issue=4&rft.spage=e0196587&rft.epage=e0196587&rft.pages=e0196587-e0196587&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0196587&rft_dat=%3Cgale_plos_%3EA536468087%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2031702583&rft_id=info:pmid/29702698&rft_galeid=A536468087&rft_doaj_id=oai_doaj_org_article_c27cf464230f413db806a3cf6a667d7f&rfr_iscdi=true |