On the mechanism of synaptic depression induced by CaMKIIN, an endogenous inhibitor of CaMKII
Activity-dependent synaptic plasticity underlies, at least in part, learning and memory processes. NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) is a major synaptic plasticity model. During LTP induction, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated, autophospho...
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| description | Activity-dependent synaptic plasticity underlies, at least in part, learning and memory processes. NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) is a major synaptic plasticity model. During LTP induction, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated, autophosphorylated and persistently translocated to the postsynaptic density, where it binds to the NMDAR. If any of these steps is inhibited, LTP is disrupted. The endogenous CaMKII inhibitor proteins CaMKIINα,β are rapidly upregulated in specific brain regions after learning. We recently showed that transient application of peptides derived from CaMKIINα (CN peptides) persistently depresses synaptic strength and reverses LTP saturation, as it allows further LTP induction in previously saturated pathways. The treatment disrupts basal CaMKII-NMDAR interaction and decreases bound CaMKII fraction in spines. To unravel CaMKIIN function and to further understand CaMKII role in synaptic strength maintenance, here we more deeply investigated the mechanism of synaptic depression induced by CN peptides (CN-depression) in rat hippocampal slices. We showed that CN-depression does not require glutamatergic synaptic activity or Ca(2+) signaling, thus discarding unspecific triggering of activity-dependent long-term depression (LTD) in slices. Moreover, occlusion experiments revealed that CN-depression and NMDAR-LTD have different expression mechanisms. We showed that CN-depression does not involve complex metabolic pathways including protein synthesis or proteasome-mediated degradation. Remarkably, CN-depression cannot be resolved in neonate rats, for which CaMKII is mostly cytosolic and virtually absent at the postsynaptic densities. Overall, our results support a direct effect of CN peptides on synaptic CaMKII-NMDAR binding and suggest that CaMKIINα,β could be critical plasticity-related proteins that may operate as cell-wide homeostatic regulators preventing saturation of LTP mechanisms or may selectively erase LTP-induced traces in specific groups of synapses. |
| doi_str_mv | 10.1371/journal.pone.0049293 |
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NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) is a major synaptic plasticity model. During LTP induction, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated, autophosphorylated and persistently translocated to the postsynaptic density, where it binds to the NMDAR. If any of these steps is inhibited, LTP is disrupted. The endogenous CaMKII inhibitor proteins CaMKIINα,β are rapidly upregulated in specific brain regions after learning. We recently showed that transient application of peptides derived from CaMKIINα (CN peptides) persistently depresses synaptic strength and reverses LTP saturation, as it allows further LTP induction in previously saturated pathways. The treatment disrupts basal CaMKII-NMDAR interaction and decreases bound CaMKII fraction in spines. To unravel CaMKIIN function and to further understand CaMKII role in synaptic strength maintenance, here we more deeply investigated the mechanism of synaptic depression induced by CN peptides (CN-depression) in rat hippocampal slices. We showed that CN-depression does not require glutamatergic synaptic activity or Ca(2+) signaling, thus discarding unspecific triggering of activity-dependent long-term depression (LTD) in slices. Moreover, occlusion experiments revealed that CN-depression and NMDAR-LTD have different expression mechanisms. We showed that CN-depression does not involve complex metabolic pathways including protein synthesis or proteasome-mediated degradation. Remarkably, CN-depression cannot be resolved in neonate rats, for which CaMKII is mostly cytosolic and virtually absent at the postsynaptic densities. Overall, our results support a direct effect of CN peptides on synaptic CaMKII-NMDAR binding and suggest that CaMKIINα,β could be critical plasticity-related proteins that may operate as cell-wide homeostatic regulators preventing saturation of LTP mechanisms or may selectively erase LTP-induced traces in specific groups of synapses.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0049293</identifier><identifier>PMID: 23145145</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Biology ; Brain ; Brain slice preparation ; Ca2+/calmodulin-dependent protein kinase II ; Calcium binding proteins ; Calcium Signaling - physiology ; Calcium signalling ; Calcium-binding protein ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - analysis ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism ; Calmodulin ; Carrier Proteins - metabolism ; Carrier Proteins - physiology ; Cerebral blood flow ; Dendritic spines ; Glutamatergic transmission ; Glutamic acid receptors (ionotropic) ; Hippocampus ; Hippocampus - metabolism ; Homeostatic plasticity ; Inhibitors ; Ischemia ; Kinases ; Learning ; Long-term depression ; Long-Term Potentiation ; Long-Term Synaptic Depression ; Medical screening ; Memory ; Metabolic pathways ; N-Methyl-D-aspartic acid receptors ; Occlusion ; Peptides ; Phosphorylation ; Plasticity ; Postsynaptic density ; Proteasomes ; Protein biosynthesis ; Protein kinases ; Protein synthesis ; Protein Transport ; Proteins ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate - metabolism ; Receptors, N-Methyl-D-Aspartate - physiology ; Regulators ; RNA, Messenger - metabolism ; Saturation ; Synapses ; Synaptic depression ; Synaptic plasticity ; Synaptic strength</subject><ispartof>PloS one, 2012-11, Vol.7 (11), p.e49293-e49293</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Gouet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>2012 Gouet et al 2012 Gouet et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-51b013c03bdf1cf9f2a55ab3c24ba10c399c7ce908928119debc32ddec7fa49f3</citedby><cites>FETCH-LOGICAL-c692t-51b013c03bdf1cf9f2a55ab3c24ba10c399c7ce908928119debc32ddec7fa49f3</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/PMC3493544/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493544/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79472,79473</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23145145$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Norris, Christopher Mark</contributor><creatorcontrib>Gouet, Camilo</creatorcontrib><creatorcontrib>Aburto, Belen</creatorcontrib><creatorcontrib>Vergara, Cecilia</creatorcontrib><creatorcontrib>Sanhueza, Magdalena</creatorcontrib><title>On the mechanism of synaptic depression induced by CaMKIIN, an endogenous inhibitor of CaMKII</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Activity-dependent synaptic plasticity underlies, at least in part, learning and memory processes. NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) is a major synaptic plasticity model. During LTP induction, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated, autophosphorylated and persistently translocated to the postsynaptic density, where it binds to the NMDAR. If any of these steps is inhibited, LTP is disrupted. The endogenous CaMKII inhibitor proteins CaMKIINα,β are rapidly upregulated in specific brain regions after learning. We recently showed that transient application of peptides derived from CaMKIINα (CN peptides) persistently depresses synaptic strength and reverses LTP saturation, as it allows further LTP induction in previously saturated pathways. The treatment disrupts basal CaMKII-NMDAR interaction and decreases bound CaMKII fraction in spines. To unravel CaMKIIN function and to further understand CaMKII role in synaptic strength maintenance, here we more deeply investigated the mechanism of synaptic depression induced by CN peptides (CN-depression) in rat hippocampal slices. We showed that CN-depression does not require glutamatergic synaptic activity or Ca(2+) signaling, thus discarding unspecific triggering of activity-dependent long-term depression (LTD) in slices. Moreover, occlusion experiments revealed that CN-depression and NMDAR-LTD have different expression mechanisms. We showed that CN-depression does not involve complex metabolic pathways including protein synthesis or proteasome-mediated degradation. Remarkably, CN-depression cannot be resolved in neonate rats, for which CaMKII is mostly cytosolic and virtually absent at the postsynaptic densities. 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physiology</topic><topic>Calcium signalling</topic><topic>Calcium-binding protein</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - analysis</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism</topic><topic>Calmodulin</topic><topic>Carrier Proteins - metabolism</topic><topic>Carrier Proteins - physiology</topic><topic>Cerebral blood flow</topic><topic>Dendritic spines</topic><topic>Glutamatergic transmission</topic><topic>Glutamic acid receptors (ionotropic)</topic><topic>Hippocampus</topic><topic>Hippocampus - metabolism</topic><topic>Homeostatic plasticity</topic><topic>Inhibitors</topic><topic>Ischemia</topic><topic>Kinases</topic><topic>Learning</topic><topic>Long-term depression</topic><topic>Long-Term Potentiation</topic><topic>Long-Term Synaptic Depression</topic><topic>Medical screening</topic><topic>Memory</topic><topic>Metabolic pathways</topic><topic>N-Methyl-D-aspartic acid receptors</topic><topic>Occlusion</topic><topic>Peptides</topic><topic>Phosphorylation</topic><topic>Plasticity</topic><topic>Postsynaptic density</topic><topic>Proteasomes</topic><topic>Protein biosynthesis</topic><topic>Protein kinases</topic><topic>Protein synthesis</topic><topic>Protein Transport</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, N-Methyl-D-Aspartate - metabolism</topic><topic>Receptors, N-Methyl-D-Aspartate - physiology</topic><topic>Regulators</topic><topic>RNA, Messenger - metabolism</topic><topic>Saturation</topic><topic>Synapses</topic><topic>Synaptic depression</topic><topic>Synaptic plasticity</topic><topic>Synaptic strength</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gouet, Camilo</creatorcontrib><creatorcontrib>Aburto, Belen</creatorcontrib><creatorcontrib>Vergara, Cecilia</creatorcontrib><creatorcontrib>Sanhueza, Magdalena</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale in Context : Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science 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 Materials Science Collection</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>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gouet, Camilo</au><au>Aburto, Belen</au><au>Vergara, Cecilia</au><au>Sanhueza, Magdalena</au><au>Norris, Christopher Mark</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>On the mechanism of synaptic depression induced by CaMKIIN, an endogenous inhibitor of CaMKII</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-11-08</date><risdate>2012</risdate><volume>7</volume><issue>11</issue><spage>e49293</spage><epage>e49293</epage><pages>e49293-e49293</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Activity-dependent synaptic plasticity underlies, at least in part, learning and memory processes. NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) is a major synaptic plasticity model. During LTP induction, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated, autophosphorylated and persistently translocated to the postsynaptic density, where it binds to the NMDAR. If any of these steps is inhibited, LTP is disrupted. The endogenous CaMKII inhibitor proteins CaMKIINα,β are rapidly upregulated in specific brain regions after learning. We recently showed that transient application of peptides derived from CaMKIINα (CN peptides) persistently depresses synaptic strength and reverses LTP saturation, as it allows further LTP induction in previously saturated pathways. The treatment disrupts basal CaMKII-NMDAR interaction and decreases bound CaMKII fraction in spines. To unravel CaMKIIN function and to further understand CaMKII role in synaptic strength maintenance, here we more deeply investigated the mechanism of synaptic depression induced by CN peptides (CN-depression) in rat hippocampal slices. We showed that CN-depression does not require glutamatergic synaptic activity or Ca(2+) signaling, thus discarding unspecific triggering of activity-dependent long-term depression (LTD) in slices. Moreover, occlusion experiments revealed that CN-depression and NMDAR-LTD have different expression mechanisms. We showed that CN-depression does not involve complex metabolic pathways including protein synthesis or proteasome-mediated degradation. Remarkably, CN-depression cannot be resolved in neonate rats, for which CaMKII is mostly cytosolic and virtually absent at the postsynaptic densities. Overall, our results support a direct effect of CN peptides on synaptic CaMKII-NMDAR binding and suggest that CaMKIINα,β could be critical plasticity-related proteins that may operate as cell-wide homeostatic regulators preventing saturation of LTP mechanisms or may selectively erase LTP-induced traces in specific groups of synapses.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23145145</pmid><doi>10.1371/journal.pone.0049293</doi><tpages>e49293</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_1326739716 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Biology Brain Brain slice preparation Ca2+/calmodulin-dependent protein kinase II Calcium binding proteins Calcium Signaling - physiology Calcium signalling Calcium-binding protein Calcium-Calmodulin-Dependent Protein Kinase Type 2 - analysis Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism Calmodulin Carrier Proteins - metabolism Carrier Proteins - physiology Cerebral blood flow Dendritic spines Glutamatergic transmission Glutamic acid receptors (ionotropic) Hippocampus Hippocampus - metabolism Homeostatic plasticity Inhibitors Ischemia Kinases Learning Long-term depression Long-Term Potentiation Long-Term Synaptic Depression Medical screening Memory Metabolic pathways N-Methyl-D-aspartic acid receptors Occlusion Peptides Phosphorylation Plasticity Postsynaptic density Proteasomes Protein biosynthesis Protein kinases Protein synthesis Protein Transport Proteins Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate - metabolism Receptors, N-Methyl-D-Aspartate - physiology Regulators RNA, Messenger - metabolism Saturation Synapses Synaptic depression Synaptic plasticity Synaptic strength |
| title | On the mechanism of synaptic depression induced by CaMKIIN, an endogenous inhibitor of CaMKII |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T01%3A11%3A17IST&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=On%20the%20mechanism%20of%20synaptic%20depression%20induced%20by%20CaMKIIN,%20an%20endogenous%20inhibitor%20of%20CaMKII&rft.jtitle=PloS%20one&rft.au=Gouet,%20Camilo&rft.date=2012-11-08&rft.volume=7&rft.issue=11&rft.spage=e49293&rft.epage=e49293&rft.pages=e49293-e49293&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0049293&rft_dat=%3Cgale_plos_%3EA477091556%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=1326739716&rft_id=info:pmid/23145145&rft_galeid=A477091556&rft_doaj_id=oai_doaj_org_article_2d7ce8b5b7884f9898be5a830740f435&rfr_iscdi=true |