Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model
Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impair...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2023-12, Vol.44 (12), p.2376-2387 |
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| creator | Yang, Lin Zhang, Qi Wu, Xue-qing Qiu, Xiao-yun Fei, Fan Lai, Nan-xi Zheng, Yu-yi Zhang, Meng-di Zhang, Qing-yang Wang, Yu Wang, Fei Xu, Ceng-lin Ruan, Ye-ping Wang, Yi Chen, Zhong |
| description | Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα
+
glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα
+
neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos
+
neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE. |
| doi_str_mv | 10.1038/s41401-023-01129-z |
| format | Article |
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+
glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα
+
neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos
+
neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.</description><identifier>ISSN: 1671-4083</identifier><identifier>ISSN: 1745-7254</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-023-01129-z</identifier><identifier>PMID: 37488426</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>Animals ; Biomedical and Life Sciences ; Biomedicine ; c-Fos protein ; Cognition ; Cognition & reasoning ; Cognitive ability ; Cognitive Dysfunction ; Comorbidity ; Convulsions & seizures ; Epilepsy ; Epilepsy, Temporal Lobe - psychology ; Excitability ; Glutamatergic transmission ; Hippocampus ; Immunology ; Internal Medicine ; Interneurons ; Kindling ; Male ; Medical Microbiology ; Mice ; Neurons ; Pattern recognition ; Pharmacology/Toxicology ; Regulatory sequences ; Seizures ; Subiculum ; Temporal lobe ; Therapeutic targets ; Vaccine ; γ-Aminobutyric acid</subject><ispartof>Acta pharmacologica Sinica, 2023-12, Vol.44 (12), p.2376-2387</ispartof><rights>The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c431t-ff7ff3bba5ed77072015b587b70528ac1edefd9bd3f47842dae40a2bf99ced033</citedby><cites>FETCH-LOGICAL-c431t-ff7ff3bba5ed77072015b587b70528ac1edefd9bd3f47842dae40a2bf99ced033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10692337/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10692337/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,27928,27929,53795,53797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37488426$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Lin</creatorcontrib><creatorcontrib>Zhang, Qi</creatorcontrib><creatorcontrib>Wu, Xue-qing</creatorcontrib><creatorcontrib>Qiu, Xiao-yun</creatorcontrib><creatorcontrib>Fei, Fan</creatorcontrib><creatorcontrib>Lai, Nan-xi</creatorcontrib><creatorcontrib>Zheng, Yu-yi</creatorcontrib><creatorcontrib>Zhang, Meng-di</creatorcontrib><creatorcontrib>Zhang, Qing-yang</creatorcontrib><creatorcontrib>Wang, Yu</creatorcontrib><creatorcontrib>Wang, Fei</creatorcontrib><creatorcontrib>Xu, Ceng-lin</creatorcontrib><creatorcontrib>Ruan, Ye-ping</creatorcontrib><creatorcontrib>Wang, Yi</creatorcontrib><creatorcontrib>Chen, Zhong</creatorcontrib><title>Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα
+
glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα
+
neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos
+
neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.</description><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>c-Fos protein</subject><subject>Cognition</subject><subject>Cognition & reasoning</subject><subject>Cognitive ability</subject><subject>Cognitive Dysfunction</subject><subject>Comorbidity</subject><subject>Convulsions & seizures</subject><subject>Epilepsy</subject><subject>Epilepsy, Temporal Lobe - psychology</subject><subject>Excitability</subject><subject>Glutamatergic transmission</subject><subject>Hippocampus</subject><subject>Immunology</subject><subject>Internal Medicine</subject><subject>Interneurons</subject><subject>Kindling</subject><subject>Male</subject><subject>Medical Microbiology</subject><subject>Mice</subject><subject>Neurons</subject><subject>Pattern recognition</subject><subject>Pharmacology/Toxicology</subject><subject>Regulatory sequences</subject><subject>Seizures</subject><subject>Subiculum</subject><subject>Temporal lobe</subject><subject>Therapeutic targets</subject><subject>Vaccine</subject><subject>γ-Aminobutyric acid</subject><issn>1671-4083</issn><issn>1745-7254</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><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>eNp9kUuLFDEUhYMozjj6B1xIwI2b0ryqUrUSaXQUBtzoOqRSN90ZUkmbVDVO_3qv0-P4WAiBPO53z83hEPKcs9ecyf5NVVwx3jAhG8a5GJrjA3LOtWobLVr1EM-d5o1ivTwjT2q9ZkwKyYfH5Exq1fdKdOfk-2YHc95CgiU4GtIujGEJOdHsaV3H4NZoC60QjmuBxrolHOwCE02wlpwqtTHCIeBTpS5vE_YegE7ggwsLytHZRqBzXitQ2IcI-3qD1wniU_LI21jh2d1-Qb5-eP9l87G5-nz5afPuqnFK8qXxXnsvx9G2MGnNtGC8Hdtej5q1oreOAw6bhnGSXmm0NFlQzIrRD4ODiUl5Qd6edPfrOMPkIC3FRrMvYbblxmQbzN-VFHZmmw-Gs24QUmpUeHWnUPK3Fepi5lAdxGgToDEjesX7nuFC9OU_6HVeS0J_SA0dGzCrDilxolzJtRbw97_hzPxM1pySNUib22TNEZte_OnjvuVXlAjIE1CxlLZQfs_-j-wPMt2z1g</recordid><startdate>20231201</startdate><enddate>20231201</enddate><creator>Yang, Lin</creator><creator>Zhang, Qi</creator><creator>Wu, Xue-qing</creator><creator>Qiu, Xiao-yun</creator><creator>Fei, Fan</creator><creator>Lai, Nan-xi</creator><creator>Zheng, Yu-yi</creator><creator>Zhang, Meng-di</creator><creator>Zhang, Qing-yang</creator><creator>Wang, Yu</creator><creator>Wang, Fei</creator><creator>Xu, Ceng-lin</creator><creator>Ruan, Ye-ping</creator><creator>Wang, Yi</creator><creator>Chen, Zhong</creator><general>Springer Nature Singapore</general><general>Nature Publishing Group</general><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>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</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>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20231201</creationdate><title>Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model</title><author>Yang, Lin ; Zhang, Qi ; Wu, Xue-qing ; Qiu, Xiao-yun ; Fei, Fan ; Lai, Nan-xi ; Zheng, Yu-yi ; Zhang, Meng-di ; Zhang, Qing-yang ; Wang, Yu ; Wang, Fei ; Xu, Ceng-lin ; Ruan, Ye-ping ; Wang, Yi ; Chen, Zhong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c431t-ff7ff3bba5ed77072015b587b70528ac1edefd9bd3f47842dae40a2bf99ced033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>c-Fos protein</topic><topic>Cognition</topic><topic>Cognition & reasoning</topic><topic>Cognitive ability</topic><topic>Cognitive Dysfunction</topic><topic>Comorbidity</topic><topic>Convulsions & seizures</topic><topic>Epilepsy</topic><topic>Epilepsy, Temporal Lobe - psychology</topic><topic>Excitability</topic><topic>Glutamatergic transmission</topic><topic>Hippocampus</topic><topic>Immunology</topic><topic>Internal Medicine</topic><topic>Interneurons</topic><topic>Kindling</topic><topic>Male</topic><topic>Medical Microbiology</topic><topic>Mice</topic><topic>Neurons</topic><topic>Pattern recognition</topic><topic>Pharmacology/Toxicology</topic><topic>Regulatory sequences</topic><topic>Seizures</topic><topic>Subiculum</topic><topic>Temporal lobe</topic><topic>Therapeutic targets</topic><topic>Vaccine</topic><topic>γ-Aminobutyric acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Lin</creatorcontrib><creatorcontrib>Zhang, Qi</creatorcontrib><creatorcontrib>Wu, Xue-qing</creatorcontrib><creatorcontrib>Qiu, Xiao-yun</creatorcontrib><creatorcontrib>Fei, Fan</creatorcontrib><creatorcontrib>Lai, Nan-xi</creatorcontrib><creatorcontrib>Zheng, Yu-yi</creatorcontrib><creatorcontrib>Zhang, Meng-di</creatorcontrib><creatorcontrib>Zhang, Qing-yang</creatorcontrib><creatorcontrib>Wang, Yu</creatorcontrib><creatorcontrib>Wang, Fei</creatorcontrib><creatorcontrib>Xu, Ceng-lin</creatorcontrib><creatorcontrib>Ruan, Ye-ping</creatorcontrib><creatorcontrib>Wang, Yi</creatorcontrib><creatorcontrib>Chen, Zhong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech 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>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</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>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Lin</au><au>Zhang, Qi</au><au>Wu, Xue-qing</au><au>Qiu, Xiao-yun</au><au>Fei, Fan</au><au>Lai, Nan-xi</au><au>Zheng, Yu-yi</au><au>Zhang, Meng-di</au><au>Zhang, Qing-yang</au><au>Wang, Yu</au><au>Wang, Fei</au><au>Xu, Ceng-lin</au><au>Ruan, Ye-ping</au><au>Wang, Yi</au><au>Chen, Zhong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacol Sin</addtitle><date>2023-12-01</date><risdate>2023</risdate><volume>44</volume><issue>12</issue><spage>2376</spage><epage>2387</epage><pages>2376-2387</pages><issn>1671-4083</issn><issn>1745-7254</issn><eissn>1745-7254</eissn><abstract>Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα
+
glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα
+
neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos
+
neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>37488426</pmid><doi>10.1038/s41401-023-01129-z</doi><tpages>12</tpages></addata></record> |
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| subjects | Animals Biomedical and Life Sciences Biomedicine c-Fos protein Cognition Cognition & reasoning Cognitive ability Cognitive Dysfunction Comorbidity Convulsions & seizures Epilepsy Epilepsy, Temporal Lobe - psychology Excitability Glutamatergic transmission Hippocampus Immunology Internal Medicine Interneurons Kindling Male Medical Microbiology Mice Neurons Pattern recognition Pharmacology/Toxicology Regulatory sequences Seizures Subiculum Temporal lobe Therapeutic targets Vaccine γ-Aminobutyric acid |
| title | Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model |
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