Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice

Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice | 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 Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice Alex Nord, Cesar Canales, Stephanie Lozano, Nicholas Frost, Karol Cichewicz, and 26 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7208668/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract CHD8 mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. Chd8 +/- mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nucleus transcriptomics (snRNA-seq), we found increased Chd8 +/- cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive Chd8 +/- and conditional Camk2a-Cre Chd8 +/- mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found Chd8 +/- mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, Chd8 haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior. Biological sciences/Neuroscience/Genetics of the nervous system Biological sciences/Computational biology and bioinformatics/Gene regulatory networks Biological sciences/Genetics/Genomics/Transcriptomics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files CanalesLozanoNatCommSuppFiguresv1.pdf Supplementary Figures CanalesLozanoNatCommAllSuppTables.xlsx Related Manuscript File Cite Share Download PDF Status: Under Review Version 1 posted 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. 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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-7208668","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":495599247,"identity":"13fb179b-7e19-4a92-a703-6b4f95ef994f","order_by":0,"name":"Alex Nord","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYNACNhsgkQBGDAwHiNOSRrqWwwxQ9URo4e8/e/BxRdn5xP725GcSD/4wyPHdSMCvReJGXrLhmXO3E2eceWYmkdjGYCxJSAvDDR4zyca224kbJBKMDRIbGBI3ENIif/4MSMs5oJb0zwYJfxjqCWoxOJAD0nIAqCXH8EECG0OCASEthjdyjA0bziUbzzjzpvBBYpuE4cwzD/BrkTt/xvBhQ5mdbH97+oaDP/7YyPMdJ2ALOpAgTfkoGAWjYBSMAuwAAP45SoWOwj9UAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-4259-7514","institution":"University of California, Davis","correspondingAuthor":true,"prefix":"","firstName":"Alex","middleName":"","lastName":"Nord","suffix":""},{"id":495599248,"identity":"e5aa697f-4144-4164-b149-8c4876f9af0d","order_by":1,"name":"Cesar Canales","email":"","orcid":"https://orcid.org/0000-0003-2505-8367","institution":"University of California, Davis","correspondingAuthor":false,"prefix":"","firstName":"Cesar","middleName":"","lastName":"Canales","suffix":""},{"id":495599249,"identity":"6384cf22-bb8e-471b-be25-d3a120d15474","order_by":2,"name":"Stephanie Lozano","email":"","orcid":"","institution":"University of California, Davis","correspondingAuthor":false,"prefix":"","firstName":"Stephanie","middleName":"","lastName":"Lozano","suffix":""},{"id":495599250,"identity":"bbce3b72-598d-416f-a2eb-9336b9f0d21f","order_by":3,"name":"Nicholas Frost","email":"","orcid":"https://orcid.org/0000-0002-2270-643X","institution":"University of Utah","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"","lastName":"Frost","suffix":""},{"id":495599251,"identity":"4a4a803c-8139-4843-b0aa-001db549ef51","order_by":4,"name":"Karol Cichewicz","email":"","orcid":"","institution":"University of California, Davis","correspondingAuthor":false,"prefix":"","firstName":"Karol","middleName":"","lastName":"Cichewicz","suffix":""},{"id":495599252,"identity":"1ef1befa-393d-459b-b88f-9f491ef58db3","order_by":5,"name":"Wellington Amaral","email":"","orcid":"https://orcid.org/0000-0003-4558-1761","institution":"University of California, Davis","correspondingAuthor":false,"prefix":"","firstName":"Wellington","middleName":"","lastName":"Amaral","suffix":""},{"id":495599253,"identity":"0a651186-f9de-4be2-9614-d394d6c43835","order_by":6,"name":"Nicholas Seban","email":"","orcid":"","institution":"The Scripps Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"","lastName":"Seban","suffix":""},{"id":495599254,"identity":"b01d682c-9bd1-4805-90e6-93f390c55049","order_by":7,"name":"Ethan Fenton","email":"","orcid":"","institution":"University of California, Davis","correspondingAuthor":false,"prefix":"","firstName":"Ethan","middleName":"","lastName":"Fenton","suffix":""},{"id":495599255,"identity":"62e7d919-59f8-4c54-a2b2-3893bc9449b0","order_by":8,"name":"A. 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mice\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7208668/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7208668/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ci\u003eCHD8\u003c/i\u003e mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. \u003ci\u003eChd8\u003csup\u003e+/-\u003c/sup\u003e\u003c/i\u003e mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nucleus transcriptomics (snRNA-seq), we found increased \u003ci\u003eChd8\u003csup\u003e+/-\u003c/sup\u003e\u003c/i\u003e cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive \u003ci\u003eChd8\u003csup\u003e+/-\u003c/sup\u003e\u003c/i\u003e and conditional \u003ci\u003eCamk2a-Cre Chd8\u003csup\u003e+/-\u003c/sup\u003e\u003c/i\u003e mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found \u003ci\u003eChd8\u003csup\u003e+/-\u003c/sup\u003e\u003c/i\u003e mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, \u003ci\u003eChd8\u003c/i\u003e haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.","manuscriptTitle":"Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-05 15:03:43","doi":"10.21203/rs.3.rs-7208668/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7776ab4c-e685-4ad3-ab23-ceea857a318d","owner":[],"postedDate":"August 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":52690751,"name":"Biological sciences/Neuroscience/Genetics of the nervous system"},{"id":52690752,"name":"Biological sciences/Computational biology and bioinformatics/Gene regulatory networks"},{"id":52690753,"name":"Biological sciences/Genetics/Genomics/Transcriptomics"}],"tags":[],"updatedAt":"2025-10-29T09:35:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-05 15:03:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7208668","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7208668","identity":"rs-7208668","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}