Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-Related Intellectual Disability

Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-Related Intellectual Disability | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-Related Intellectual Disability Jill Silverman, Timothy Fenton, Olivia Haouchine, Elizabeth Hallam, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4067746/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Oct, 2024 Read the published version in Translational Psychiatry → Version 1 posted 12 You are reading this latest preprint version Abstract Disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability (SRID). Without functional SynGAP1 protein, individuals are developmentally delayed and have prominent features of intellectual disability, motor impairments, and epilepsy. Over the past two decades, there have been numerous discoveries indicting the critical role of Syngap1. Several rodent models with a loss of Syngap1 have been engineered identifying precise roles in neuronal structure and function, as well as key biochemical pathways key for synapse integrity. Homozygous loss of Syngap1 is lethal. Heterozygous mutations of Syngap1 result in a broad range of behavioral phenotypes. Our in vivo functional data, using the mouse model from the Huganir laboratory, corroborated earlier reported behaviors including robust hyperactivity and deficits in learning and memory in young adults. In extension, we report impairments in slow wave sleep, a critical component of the domain of sleep. We characterized Syngap1+/- mice by using neurophysiology collected with wireless, telemetric electroencephalography (EEG). Syngap1+/- mice also exhibited elevated spiking events and spike trains, in addition to elevated power, most notably in the delta frequency band. For the first time, we illustrated how primary neurons from Syngap1+/- mice function and display increased network firing activity, greater bursts, and shorter inter-burst intervals between peaks by employing high density microelectrode arrays (HD-MEA). Our reported data bridge in-vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate quantitative, translational biomarkers in vivo and in vitro that can be utilized for the development of and efficacy assessment of targeted treatments for SRID. Biological sciences/Neuroscience Health sciences/Biomarkers/Prognostic markers Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders Syngap1 neurodevelopmental disorder mouse model behavior microelectrode arrays sleep cognition sleep physiology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files SupplementaryResultsandSupplementalFiguresandLegendsMarch92024.docx Cite Share Download PDF Status: Published Journal Publication published 02 Oct, 2024 Read the published version in Translational Psychiatry → Version 1 posted Editorial decision: revise 14 May, 2024 Review # 3 received at journal 12 Apr, 2024 Review # 2 received at journal 10 Apr, 2024 Review # 1 received at journal 07 Apr, 2024 Reviewer # 3 agreed at journal 19 Mar, 2024 Reviewer # 2 agreed at journal 19 Mar, 2024 Reviewer # 1 agreed at journal 16 Mar, 2024 Reviewers invited by journal 15 Mar, 2024 Submission checks completed at journal 13 Mar, 2024 First submitted to journal 12 Mar, 2024 Unknown event 11 Mar, 2024 Editor assigned by journal 10 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4067746","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":280195910,"identity":"f017f65e-4624-493f-833a-b013eb76710f","order_by":0,"name":"Jill Silverman","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYBACxgbGxgMQJjOQZgMjBgYe/FoaoFrYEojTAgJQLTwGUPUEtDD3H244zFNxL5p/ds83iR9ldol9/AcYH7xtw+OwGYlALWeKc2fcObtNsudccmKbRAKz4Vy8WhgbDs5sS8htuJG7TZqxjdmYTYKBTZoXn5b+g0At/xJy59/IeQbUUm/Mxn+A/TdeLQ2JDQc+NiTkbriRwwbUcliOjSGBjRmvFqBfDnw4lpC78UaasWXPueNybBKJzZJzzuHWYth//OGDhJqE3Hk3kh/e+FFWzSPff/jghzdleLQ0YHMsbvVAII9XdhSMglEwCkYBCAAAOFxWLXqGyQUAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-9357-5476","institution":"MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jill","middleName":"","lastName":"Silverman","suffix":""},{"id":280195911,"identity":"73a68328-4813-4e90-baa3-d78bb66a121a","order_by":1,"name":"Timothy Fenton","email":"","orcid":"","institution":"University of California Davis School of 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Nord","email":"","orcid":"https://orcid.org/0000-0003-4259-7514","institution":"University of California, Davis","correspondingAuthor":false,"prefix":"","firstName":"Alex","middleName":"","lastName":"Nord","suffix":""},{"id":280195919,"identity":"07312b80-d44e-40b5-b5cf-34d0b9e3bf33","order_by":9,"name":"Anna Adhikari","email":"","orcid":"","institution":"University of California Davis School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Adhikari","suffix":""},{"id":280195920,"identity":"c1d71054-f603-4003-b037-d012c3c72144","order_by":10,"name":"Darlene Rahbarian","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Darlene","middleName":"","lastName":"Rahbarian","suffix":""}],"badges":[],"createdAt":"2024-03-10 21:10:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4067746/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4067746/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41398-024-03077-6","type":"published","date":"2024-10-02T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53011600,"identity":"5c81a4da-0b99-4b89-9c7a-bc4eea51b349","added_by":"auto","created_at":"2024-03-19 15:37:00","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1068652,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eSyngap1+/- \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003emice had a significant decrease in the protein expression of SynGAP1 compared to \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eSyngap1+/+\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003emice.\u003c/strong\u003e \u003cstrong\u003e(A)\u003c/strong\u003eSynGAP1 and Gapdh protein expression in \u003cem\u003eSyngap1+/+\u003c/em\u003eand \u003cem\u003eSyngap1+/-\u003c/em\u003emice at PND42. Western Blot analysis of SynGAP1 (140kDa) shows a decrease in expression of SynGAP1 in the \u003cem\u003eSyngap1+/- \u003c/em\u003emice. \u003cstrong\u003e(B)\u003c/strong\u003e Quantification of SynGAP1 protein expression normalized using Gapdh constitutive expression. SynGAP1 protein expression was significantly decreased to 41% in \u003cem\u003eSyngap1+/- \u003c/em\u003ebrains as compared to \u003cem\u003eSyngap1+/+ \u003c/em\u003elittermates. \u003cstrong\u003e(C)\u003c/strong\u003e Representative mouse brain coronal section from PND60 \u003cem\u003eSyngap1+/+\u003c/em\u003eanimal shows broad SynGAP1 protein expression through immunostaining (red). DAPI staining (nuclei, blue) helps identify brain structures. Boxes indicate magnified areas. Scale bars = 100 µm. Data was analyzed using a Student’s t-test and is expressed as mean ± S.E.M. *\u003cem\u003eP\u003c/em\u003e = 0.0051. (+/+ \u003cem\u003eN\u003c/em\u003e = 3, \u003cem\u003eSyngap+/- N \u003c/em\u003e= 3).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4067746/v1/b2f7359327d3540559c3209f.jpg"},{"id":53011599,"identity":"904d9939-a15c-4533-83c3-e194cfd54f45","added_by":"auto","created_at":"2024-03-19 15:37:00","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":38565,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eSyngap1+/-\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003emice showed elevated motor activity and impaired cognition when behavior was assessed.\u003c/strong\u003e \u003cstrong\u003e(A)\u003c/strong\u003e Horizontal activity, \u003cstrong\u003e(B)\u003c/strong\u003e total activity, and \u003cstrong\u003e(C)\u003c/strong\u003e center time were all significantly increased when compared to \u003cem\u003eSyngap1+/+\u003c/em\u003e mice. Horizontal activity, total activity, and center time were analyzed using a repeated measures ANOVA. \u003cstrong\u003e(D)\u003c/strong\u003e Total activity over 30 minutes was compared with a Student’s t-test. \u003cstrong\u003e(E)\u003c/strong\u003e \u003cem\u003eSyngap1+/-\u003c/em\u003e mice showed no preference for the novel object when compared to wildtype mice. \u003cstrong\u003e(F)\u003c/strong\u003eIn the spontaneous alternation task, there was no difference in the percentage of alternations between wildtype\u003cem\u003e \u003c/em\u003eand \u003cem\u003eSyngap1+/-\u003c/em\u003e animals. \u003cstrong\u003e(G)\u003c/strong\u003e \u003cem\u003eSyngap1+/-\u003c/em\u003e mice made significantly more total transitions between arms in the spontaneous alternation task when compared to wildtype animals. Groups compared with a Student’s t-test. Data are expressed as mean ± S.E.M. * = \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05, **** = \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4067746/v1/7378cdeb918d3ae89616de02.jpg"},{"id":53012793,"identity":"1ce2815e-2b0a-41b8-9b77-9c76101c03d6","added_by":"auto","created_at":"2024-03-19 15:45:00","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":41589,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eSyngap1+/- \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003emice displayed elevated delta and theta power.\u003c/strong\u003e Surface EEG was collected using wireless telemetry and power spectral densities were compared at delta (.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), and gamma (30-50 Hz) frequencies. \u003cstrong\u003e(A)\u003c/strong\u003e Power spectral density collected from \u003cem\u003eSyngap1+/- \u003c/em\u003emice was increased compared to \u003cem\u003eSyngap1+/+\u003c/em\u003e mice. \u003cstrong\u003e(B)\u003c/strong\u003e Delta and theta frequency power were \u0026nbsp;significantly increased in \u003cem\u003eSyngap1+/- \u003c/em\u003emice. \u003cstrong\u003e(C)\u003c/strong\u003e Representative power distribution of \u003cem\u003eSyngap1+/+\u003c/em\u003emice and \u0026nbsp;\u003cem\u003eSyngap1+/-\u003c/em\u003e mice over a 10-minute period illustrates elevated delta and theta power in \u003cem\u003eSyngap1+/-\u003c/em\u003emice. \u003cstrong\u003e(D)\u003c/strong\u003e \u0026nbsp;\u003cem\u003eSyngap1+/-\u003c/em\u003emice exhibited elevated spike train counts. \u003cstrong\u003e(E)\u003c/strong\u003e \u003cem\u003eSyngap1+/- \u003c/em\u003emice displayed significantly \u0026nbsp;increased total spike train duration. \u003cstrong\u003e(F)\u003c/strong\u003e Representative EEG traces of \u003cem\u003eSyngap1+/+ \u003c/em\u003eand \u003cem\u003eSyngap1+/- \u003c/em\u003emice \u0026nbsp;recorded over 10 minutes. Data were analyzed using a two-way ANOVA between genotype and \u0026nbsp;frequency and Sidak’s post hoc analysis where applicable (A,B), or with Student’s t-test (D,E). Data are \u0026nbsp;expressed as mean ± S.E.M. * = \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, ** = \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01, *** = \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.001 **** = \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4067746/v1/37d094638b293b27d23f02ca.jpg"},{"id":53011598,"identity":"be173410-5ff7-4ca3-9763-1835c9fa83c6","added_by":"auto","created_at":"2024-03-19 15:37:00","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":38214,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eSyngap1+/- \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003emice displayed altered EEG sleep signatures.\u003c/strong\u003e \u003cstrong\u003e(A)\u003c/strong\u003e Schematic of wireless \u0026nbsp;telemetric recording system and representative signals from the four sleep stages. EEG signal is recorded \u0026nbsp;while mice are in their home cage and allowed to move freely. \u003cstrong\u003e(B)\u003c/strong\u003e Active wake percentage determined \u0026nbsp;from EMG recording and integrated accelerometer when subject displayed movement while awake. \u0026nbsp;\u003cem\u003eSyngap1+/- \u003c/em\u003emice displayed elevated active wake time. \u0026nbsp;\u003cstrong\u003e(C)\u003c/strong\u003ePercentage of wake across 72 hours where \u0026nbsp;animals were not actively moving. \u003cem\u003eSyngap1+/- \u003c/em\u003emice showed reduced wake compared to \u003cem\u003eSyngap1+/+ \u003c/em\u003emice \u0026nbsp;\u003cstrong\u003e(D)\u003c/strong\u003e Slow wave sleep percentage was decreased in \u003cem\u003eSyngap1+/- \u003c/em\u003emice. \u003cstrong\u003e(E)\u003c/strong\u003e Paradoxical sleep percentage \u0026nbsp;from 72 hours of recording trended lower in \u003cem\u003eSyngap1+/- \u003c/em\u003emice. Data were analyzed using Student’s \u0026nbsp;unpaired t-test. Data are expressed as mean ± S.E.M. * = \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, ** = \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.01.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4067746/v1/f7444e9404bc147b3280f81f.jpg"},{"id":53011602,"identity":"f2f74c37-d13d-4de6-bcfb-09df7f23c4dc","added_by":"auto","created_at":"2024-03-19 15:37:00","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":65857,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrimary neurons from \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eSyngap1+/- \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003emice displayed increased network firing activity when \u003c/strong\u003e\u0026nbsp;\u003cstrong\u003emeasured with high-density microelectrode arrays (HD-MEAs).\u003c/strong\u003e \u003cstrong\u003e(A)\u003c/strong\u003e Firing rate from the entire chip \u0026nbsp;area. \u003cstrong\u003e(B)\u003c/strong\u003e1024 electrodes with the highest firing rates were chosen to conduct a “Network Activity Scan”. \u0026nbsp;\u003cstrong\u003e(C)\u003c/strong\u003e Representative raster plot and \u003cstrong\u003e(E)\u003c/strong\u003e network activity plot of \u003cem\u003eSyngap1+/+ \u003c/em\u003eprimary neurons.\u003cem\u003e \u003c/em\u003e\u003cstrong\u003e(D)\u003c/strong\u003e\u003cem\u003e \u003c/em\u003e\u0026nbsp;\u003cem\u003eSyngap1+/- \u003c/em\u003eraster plot and \u003cstrong\u003e(F)\u003c/strong\u003e network activity plot exhibit increased activity. 1024 electrodes were \u0026nbsp;recorded simultaneously and plotted on the y-axis of raster plots.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4067746/v1/290c55b5db2fbe68de9a17bd.jpg"},{"id":53012795,"identity":"60507335-dfc7-4465-ae36-924ba5d7c7d1","added_by":"auto","created_at":"2024-03-19 15:45:00","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":54877,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eSyngap1+/- \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003emice displayed increased bursting activity when measured on HD-MEAs.\u003c/strong\u003e \u003cstrong\u003e(A)\u003c/strong\u003e \u0026nbsp;Spikes per burst in \u003cem\u003eSyngap1+/+\u003c/em\u003e and \u003cem\u003eSyngap1+/- \u003c/em\u003emice. \u003cstrong\u003e(B)\u003c/strong\u003e Inter burst interval (IBI) was measured as time between burst peaks. A reduced IBI was observed in\u003cem\u003e Syngap1+/-\u003c/em\u003eanimals on DIVs 21, 27, and 29. \u003cstrong\u003e(C)\u003c/strong\u003e The \u0026nbsp;total number of bursts over the five-minute recording was compared. \u003cem\u003eSyngap1+/-\u003c/em\u003e mice exhibited an \u0026nbsp;increased number of bursts on all days after DIV21. \u003cstrong\u003e(D)\u003c/strong\u003e \u003cem\u003eSyngap1+/-\u003c/em\u003e mice had a longer burst duration on \u0026nbsp;DIV29 when compared to \u003cem\u003eSyngap1+/+\u003c/em\u003emice. Data were analyzed using a two-way ANOVA. Data are \u0026nbsp;expressed as mean ± S.E.M. * = \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, ** = \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01, *** = \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001 **** = \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4067746/v1/6a9bc351d6dd3f60c4b17667.jpg"},{"id":65819487,"identity":"94d5916c-b0a8-487b-86f9-a05e2d4b178e","added_by":"auto","created_at":"2024-10-03 07:09:37","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1915432,"visible":true,"origin":"","legend":"","description":"","filename":"RevisionSyngap1TPMarch112024Clean.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4067746/v1_covered_f82d2ab9-aaaf-492b-8f91-e4d1d7c660a0.pdf"},{"id":53012794,"identity":"f30a746a-7c59-4a96-a892-4cafd96b9fb7","added_by":"auto","created_at":"2024-03-19 15:45:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":558148,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementaryResultsandSupplementalFiguresandLegendsMarch92024.docx","url":"https://assets-eu.researchsquare.com/files/rs-4067746/v1/aaa947a6740f6da28f58dd6c.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-Related Intellectual Disability","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Syngap1, neurodevelopmental disorder, mouse model, behavior, microelectrode arrays, sleep, cognition, sleep, physiology","lastPublishedDoi":"10.21203/rs.3.rs-4067746/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4067746/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability (SRID). Without functional SynGAP1 protein, individuals are developmentally delayed and have prominent features of intellectual disability, motor impairments, and epilepsy. Over the past two decades, there have been numerous discoveries indicting the critical role of Syngap1. Several rodent models with a loss of Syngap1 have been engineered identifying precise roles in neuronal structure and function, as well as key biochemical pathways key for synapse integrity. Homozygous loss of Syngap1 is lethal. Heterozygous mutations of Syngap1 result in a broad range of behavioral phenotypes. Our in vivo functional data, using the mouse model from the Huganir laboratory, corroborated earlier reported behaviors including robust hyperactivity and deficits in learning and memory in young adults. In extension, we report impairments in slow wave sleep, a critical component of the domain of sleep. We characterized Syngap1+/- mice by using neurophysiology collected with wireless, telemetric electroencephalography (EEG). Syngap1+/- mice also exhibited elevated spiking events and spike trains, in addition to elevated power, most notably in the delta frequency band. For the first time, we illustrated how primary neurons from Syngap1+/- mice function and display increased network firing activity, greater bursts, and shorter inter-burst intervals between peaks by employing high density microelectrode arrays (HD-MEA). Our reported data bridge in-vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate quantitative, translational biomarkers in vivo and in vitro that can be utilized for the development of and efficacy assessment of targeted treatments for SRID.","manuscriptTitle":"Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-Related Intellectual Disability","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-19 15:36:55","doi":"10.21203/rs.3.rs-4067746/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-05-14T13:25:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-04-12T20:44:22+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-04-10T20:15:55+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-04-07T15:39:54+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-03-19T15:35:26+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-03-19T12:00:48+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-03-16T23:42:13+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-03-16T02:10:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-13T10:52:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"Translational Psychiatry","date":"2024-03-12T23:03:21+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-03-11T11:15:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-10T21:05:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"53bd7e64-10d2-4cad-a7d7-3c84640940be","owner":[],"postedDate":"March 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":29512558,"name":"Biological sciences/Neuroscience"},{"id":29512559,"name":"Health sciences/Biomarkers/Prognostic markers"},{"id":29512560,"name":"Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders"}],"tags":[],"updatedAt":"2024-10-03T07:09:14+00:00","versionOfRecord":{"articleIdentity":"rs-4067746","link":"https://doi.org/10.1038/s41398-024-03077-6","journal":{"identity":"translational-psychiatry","isVorOnly":false,"title":"Translational Psychiatry"},"publishedOn":"2024-10-02 04:00:00","publishedOnDateReadable":"October 2nd, 2024"},"versionCreatedAt":"2024-03-19 15:36:55","video":"","vorDoi":"10.1038/s41398-024-03077-6","vorDoiUrl":"https://doi.org/10.1038/s41398-024-03077-6","workflowStages":[]},"version":"v1","identity":"rs-4067746","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4067746","identity":"rs-4067746","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}