Calcium-based input timing learning

Calcium-based input timing learning | 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 Calcium-based input timing learning shirin shafiee kamalabad, Sebastian Schmitt, Christian Tetzlaff This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6545452/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Feb, 2026 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Abstract Stimulus-triggered synaptic plasticity is the foundation of learning and crucial cognitive abilities. Although numerous computational models have investigated plasticity within networks of point neurons, dendritic integration provides superior computational capacity compared to these simplistic models, highlighting the significance of dendrites and their spines—small, specialized protrusions that serve as loci for synaptic plasticity. Synaptic plasticity can be categorized into two forms: homosynaptic plasticity, involving changes at directly stimulated synapses, and heterosynaptic plasticity, involving changes at non-stimulated synapses. For homosynaptic plasticity, the Ca 2+ -hypothesis identifies the calcium concentration within a stimulated dendritic spine as the key mediator. In contrast, although theoretical studies attribute important roles such as synaptic competition and cooperation to heterosynaptic plasticity, experimental evidence remains ambiguous. By integrating insights from Ca 2+ -dependent homosynaptic plasticity with data on dendritic Ca 2+ -dynamics, we demonstrate that calcium influx into a stimulated spine can diffuse to neighboring spines, triggering heterosynaptic effects. To investigate this, we developed a mathematical model characterizing the temporal and spatial dynamics of calcium in dendrites in response to different inputs. Our model explains experimental ambiguities and extends the Ca 2+ -hypothesis to heterosynaptic plasticity. Notably, it predicts input-timing, distance between spines, and local diffusion properties modulate synaptic changes, revealing a novel mechanism for dendritic computation. Biological sciences/Neuroscience/Computational neuroscience/Biophysical models Biological sciences/Neuroscience/Learning and memory/Long-term memory Diffusion Heterosynaptic plasticity Dendritic spines Calcium signaling Spike-timing-dependent plasticity Dendritic computation Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryShafieeetal.pdf Supplementary information : Calcium-based input timing learning Cite Share Download PDF Status: Published Journal Publication published 20 Feb, 2026 Read the published version in Communications Biology → 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-6545452","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":452188057,"identity":"e4123bfd-14ed-4df3-a2e0-9b580e368048","order_by":0,"name":"shirin shafiee kamalabad","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0009-7271-8939","institution":"University of Göttingen and University Medical Center Göttingen","correspondingAuthor":true,"prefix":"","firstName":"shirin","middleName":"shafiee","lastName":"kamalabad","suffix":""},{"id":452188058,"identity":"53d2654e-8c81-44b8-934a-bf7b9334aa9f","order_by":1,"name":"Sebastian Schmitt","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sebastian","middleName":"","lastName":"Schmitt","suffix":""},{"id":452188059,"identity":"664a164c-6e76-46ba-82f7-6a8a2d6ada6e","order_by":2,"name":"Christian Tetzlaff","email":"","orcid":"","institution":"University Medial Center Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Tetzlaff","suffix":""}],"badges":[],"createdAt":"2025-04-28 08:11:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6545452/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6545452/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s42003-026-09719-3","type":"published","date":"2026-02-20T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":104777372,"identity":"7306aafc-c552-44ee-bffa-90dd6bcbb2fa","added_by":"auto","created_at":"2026-03-17 07:11:05","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4918400,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ManuscriptShafieeetal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6545452/v1_covered_62b4612d-82b8-430c-8336-dd48d4f14834.pdf"},{"id":82233153,"identity":"712a84e2-975c-4988-a5fa-eacebd1ed1fe","added_by":"auto","created_at":"2025-05-08 06:32:47","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10313829,"visible":true,"origin":"","legend":"Supplementary information : Calcium-based input timing learning","description":"","filename":"SupplementaryShafieeetal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6545452/v1/8625d532cecd1b7e1253fc70.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Calcium-based input timing learning","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":"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":"Diffusion, Heterosynaptic plasticity, Dendritic spines; Calcium signaling, Spike-timing-dependent plasticity, Dendritic computation","lastPublishedDoi":"10.21203/rs.3.rs-6545452/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6545452/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Stimulus-triggered synaptic plasticity is the foundation of learning and crucial cognitive abilities. Although numerous computational models have investigated plasticity within networks of point neurons, dendritic integration provides superior computational capacity compared to these simplistic models, highlighting the significance of dendrites and their spines—small, specialized protrusions that serve as loci for synaptic plasticity. Synaptic plasticity can be categorized into two forms: homosynaptic plasticity, involving changes at directly stimulated synapses, and heterosynaptic plasticity, involving changes at non-stimulated synapses. For homosynaptic plasticity, the Ca\u003csup\u003e2+\u003c/sup\u003e-hypothesis identifies the calcium concentration within a stimulated dendritic spine as the key mediator. In contrast, although theoretical studies attribute important roles such as synaptic competition and cooperation to heterosynaptic plasticity, experimental evidence remains ambiguous. By integrating insights from Ca\u003csup\u003e2+\u003c/sup\u003e-dependent homosynaptic plasticity with data on dendritic Ca\u003csup\u003e2+\u003c/sup\u003e-dynamics, we demonstrate that calcium influx into a stimulated spine can diffuse to neighboring spines, triggering heterosynaptic effects. To investigate this, we developed a mathematical model characterizing the temporal and spatial dynamics of calcium in dendrites in response to different inputs. Our model explains experimental ambiguities and extends the Ca\u003csup\u003e2+\u003c/sup\u003e-hypothesis to heterosynaptic plasticity. 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