Synaptotagmin-7–mediated activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants
Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NM...
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| Veröffentlicht in: | PLoS biology 2021-07, Vol.19 (7), p.e3001323-e3001323 |
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| creator | Wang, Qiu-Wen Wang, Ying-Han Wang, Bing Chen, Yun Lu, Si-Yao Yao, Jun |
| description | Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NMDARs that significantly contribute to mental illness. In mouse hippocampal neurons lacking Syt1/Doc2, Syt7 inactivation largely diminishes spontaneous release. Using 2 approaches, including measuring Ca2+ dose response and substituting extracellular Ca2+ with Sr2+, we detect that Syt7 directly triggers spontaneous release via its Ca2+ binding motif to activate GluN2B-NMDARs. Furthermore, modifying the localization of Syt7 in the active zone still allows Syt7 to drive spontaneous release, but the GluN2B-NMDAR activity is abolished. Finally, Syt7 SNPs identified in bipolar disorder patients destroy the function of Syt7 in spontaneous release in patient iPSC-derived and mouse hippocampal neurons. Therefore, Syt7 could contribute to neuropsychiatric disorders through driving spontaneous glutamate release. |
| doi_str_mv | 10.1371/journal.pbio.3001323 |
| format | Article |
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Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NMDARs that significantly contribute to mental illness. In mouse hippocampal neurons lacking Syt1/Doc2, Syt7 inactivation largely diminishes spontaneous release. Using 2 approaches, including measuring Ca2+ dose response and substituting extracellular Ca2+ with Sr2+, we detect that Syt7 directly triggers spontaneous release via its Ca2+ binding motif to activate GluN2B-NMDARs. Furthermore, modifying the localization of Syt7 in the active zone still allows Syt7 to drive spontaneous release, but the GluN2B-NMDAR activity is abolished. Finally, Syt7 SNPs identified in bipolar disorder patients destroy the function of Syt7 in spontaneous release in patient iPSC-derived and mouse hippocampal neurons. Therefore, Syt7 could contribute to neuropsychiatric disorders through driving spontaneous glutamate release.</description><identifier>ISSN: 1545-7885</identifier><identifier>ISSN: 1544-9173</identifier><identifier>EISSN: 1545-7885</identifier><identifier>DOI: 10.1371/journal.pbio.3001323</identifier><identifier>PMID: 34228711</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Biology and Life Sciences ; Bipolar disorder ; Calcium (extracellular) ; Calcium ions ; Cell receptors ; CRISPR ; Exocytosis ; Genes ; Genetic aspects ; Glutamate receptors ; Glutamic acid receptors ; Hippocampus ; Identification and classification ; Inactivation ; Ligands ; Localization ; Medicine and Health Sciences ; Membrane proteins ; Mental disorders ; Methyl aspartate ; N-Methyl-D-aspartic acid receptors ; Neurons ; Properties ; Proteins ; Quantitative analysis ; Sensors ; Short Reports ; Social Sciences ; Synapses ; Synaptotagmin</subject><ispartof>PLoS biology, 2021-07, Vol.19 (7), p.e3001323-e3001323</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Wang 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>2021 Wang et al 2021 Wang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c672t-f22f3f3af00878c6c8f9dd8339de7bfaef6d22fbf9b223c90ae92d080d49a17e3</citedby><cites>FETCH-LOGICAL-c672t-f22f3f3af00878c6c8f9dd8339de7bfaef6d22fbf9b223c90ae92d080d49a17e3</cites><orcidid>0000-0002-4916-3412 ; 0000-0002-8278-2696 ; 0000-0002-8708-7799</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/PMC8284830/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284830/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids></links><search><contributor>Hughson, Frederick M.</contributor><creatorcontrib>Wang, Qiu-Wen</creatorcontrib><creatorcontrib>Wang, Ying-Han</creatorcontrib><creatorcontrib>Wang, Bing</creatorcontrib><creatorcontrib>Chen, Yun</creatorcontrib><creatorcontrib>Lu, Si-Yao</creatorcontrib><creatorcontrib>Yao, Jun</creatorcontrib><title>Synaptotagmin-7–mediated activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants</title><title>PLoS biology</title><description>Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NMDARs that significantly contribute to mental illness. In mouse hippocampal neurons lacking Syt1/Doc2, Syt7 inactivation largely diminishes spontaneous release. Using 2 approaches, including measuring Ca2+ dose response and substituting extracellular Ca2+ with Sr2+, we detect that Syt7 directly triggers spontaneous release via its Ca2+ binding motif to activate GluN2B-NMDARs. Furthermore, modifying the localization of Syt7 in the active zone still allows Syt7 to drive spontaneous release, but the GluN2B-NMDAR activity is abolished. Finally, Syt7 SNPs identified in bipolar disorder patients destroy the function of Syt7 in spontaneous release in patient iPSC-derived and mouse hippocampal neurons. Therefore, Syt7 could contribute to neuropsychiatric disorders through driving spontaneous glutamate release.</description><subject>Biology and Life Sciences</subject><subject>Bipolar disorder</subject><subject>Calcium (extracellular)</subject><subject>Calcium ions</subject><subject>Cell receptors</subject><subject>CRISPR</subject><subject>Exocytosis</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Glutamate receptors</subject><subject>Glutamic acid receptors</subject><subject>Hippocampus</subject><subject>Identification and classification</subject><subject>Inactivation</subject><subject>Ligands</subject><subject>Localization</subject><subject>Medicine and Health Sciences</subject><subject>Membrane proteins</subject><subject>Mental disorders</subject><subject>Methyl aspartate</subject><subject>N-Methyl-D-aspartic acid receptors</subject><subject>Neurons</subject><subject>Properties</subject><subject>Proteins</subject><subject>Quantitative analysis</subject><subject>Sensors</subject><subject>Short Reports</subject><subject>Social 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activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants</title><author>Wang, Qiu-Wen ; Wang, Ying-Han ; Wang, Bing ; Chen, Yun ; Lu, Si-Yao ; Yao, Jun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c672t-f22f3f3af00878c6c8f9dd8339de7bfaef6d22fbf9b223c90ae92d080d49a17e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Biology and Life Sciences</topic><topic>Bipolar disorder</topic><topic>Calcium (extracellular)</topic><topic>Calcium ions</topic><topic>Cell receptors</topic><topic>CRISPR</topic><topic>Exocytosis</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Glutamate receptors</topic><topic>Glutamic acid receptors</topic><topic>Hippocampus</topic><topic>Identification and classification</topic><topic>Inactivation</topic><topic>Ligands</topic><topic>Localization</topic><topic>Medicine and Health 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Qiu-Wen</au><au>Wang, Ying-Han</au><au>Wang, Bing</au><au>Chen, Yun</au><au>Lu, Si-Yao</au><au>Yao, Jun</au><au>Hughson, Frederick M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synaptotagmin-7–mediated activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants</atitle><jtitle>PLoS biology</jtitle><date>2021-07-06</date><risdate>2021</risdate><volume>19</volume><issue>7</issue><spage>e3001323</spage><epage>e3001323</epage><pages>e3001323-e3001323</pages><issn>1545-7885</issn><issn>1544-9173</issn><eissn>1545-7885</eissn><abstract>Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NMDARs that significantly contribute to mental illness. In mouse hippocampal neurons lacking Syt1/Doc2, Syt7 inactivation largely diminishes spontaneous release. Using 2 approaches, including measuring Ca2+ dose response and substituting extracellular Ca2+ with Sr2+, we detect that Syt7 directly triggers spontaneous release via its Ca2+ binding motif to activate GluN2B-NMDARs. Furthermore, modifying the localization of Syt7 in the active zone still allows Syt7 to drive spontaneous release, but the GluN2B-NMDAR activity is abolished. Finally, Syt7 SNPs identified in bipolar disorder patients destroy the function of Syt7 in spontaneous release in patient iPSC-derived and mouse hippocampal neurons. Therefore, Syt7 could contribute to neuropsychiatric disorders through driving spontaneous glutamate release.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>34228711</pmid><doi>10.1371/journal.pbio.3001323</doi><orcidid>https://orcid.org/0000-0002-4916-3412</orcidid><orcidid>https://orcid.org/0000-0002-8278-2696</orcidid><orcidid>https://orcid.org/0000-0002-8708-7799</orcidid><oa>free_for_read</oa></addata></record> |
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| source | DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Biology and Life Sciences Bipolar disorder Calcium (extracellular) Calcium ions Cell receptors CRISPR Exocytosis Genes Genetic aspects Glutamate receptors Glutamic acid receptors Hippocampus Identification and classification Inactivation Ligands Localization Medicine and Health Sciences Membrane proteins Mental disorders Methyl aspartate N-Methyl-D-aspartic acid receptors Neurons Properties Proteins Quantitative analysis Sensors Short Reports Social Sciences Synapses Synaptotagmin |
| title | Synaptotagmin-7–mediated activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants |
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