Stochastic tissue environment expands spatial limits of synaptic and astrocytic glutamate actions

Stochastic tissue environment expands spatial limits of synaptic and astrocytic glutamate actions | 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 Stochastic tissue environment expands spatial limits of synaptic and astrocytic glutamate actions Dmitri Rusakov, Leonid Savtchenko, Thomas Jensen, Kaiyu Zheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6066377/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract The point precision of excitatory transmission relies on high-affinity astrocytic transporters that rapidly buffer glutamate escaping from the synaptic cleft. While numerous theoretical models have supported this concept, experimental findings indicate that glutamate can diffuse farther than predicted, at times reaching receptors at neighbouring synapses. This challenges the classical view of neural networks as operating through strictly one-to-one synaptic connections. Even less is understood about the fate of glutamate released by astrocytes, as it must bypass the buffering effect of astrocytic transporters located in the immediate vicinity. We hypothesized that this mismatch between experiment and theory stems, at least in part, from a key assumption in existing biophysical models, that excitatory synapses are uniformly surrounded by transporter-rich neuropil. In reality, synapses are embedded within a complex environment composed of cellular structures with highly variable shapes and positions, of which only a fraction are astrocytic processes. To address this, we developed and empirically constrained a conceptually novel in silico model of synaptic neuropil, in which glutamate diffuses within a stochastically generated tissue environment partially occupied by transporter-expressing astrocytic processes. Our simulations predict that glutamate released from either synapses or astrocytes can potentially activate high-affinity receptors, and desensitize AMPA receptors, beyond one micron from the release site, thus influencing dozens of nearby synapses. While this prediction helps to resolve the long-standing debate, experimental studies of glutamate’s actions in the intact brain are needed to establish the precise physiological relevance of these findings. Biological sciences/Neuroscience/Synaptic transmission/Neurotransmitters Biological sciences/Neuroscience/Cellular neuroscience Biological sciences/Neuroscience/Glial biology/Astrocyte Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryFigs.pdf Supplementary Figures Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-6066377","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":462343790,"identity":"517d8921-7629-4bd2-bdbe-7382f5685278","order_by":0,"name":"Dmitri Rusakov","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYDCCA2AygYGBvYGB4QGYw0asFp4DYIoULRIJRGrhO8D7TPJHTZqcwc03hh8SGOzkGSTSEvBqkTzAbibNcyzH2OB2jjHQomTDBom0A3i1GBxgY5NmYKtInDk7xwzoMOYEBon0BoJaJH/8A2qZeQakpZ44LRK8bTmJ/RI8IC2HgVoIOEzyMBuzNW9fmjE/T1qxRILBccM2nmcJeLXwHW9jvPnjW7IcG/vhjR8+VFTL87OnGeDVwsCM6k7CETkKRsEoGAWjgAgAAP+MOzXMr+1nAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-9539-9947","institution":"University College London","correspondingAuthor":true,"prefix":"","firstName":"Dmitri","middleName":"","lastName":"Rusakov","suffix":""},{"id":462343791,"identity":"17d61139-88be-4ecd-90b1-d218c06622c9","order_by":1,"name":"Leonid Savtchenko","email":"","orcid":"","institution":"UCL Institute of Neurology","correspondingAuthor":false,"prefix":"","firstName":"Leonid","middleName":"","lastName":"Savtchenko","suffix":""},{"id":462343792,"identity":"5170cdd4-80d9-40f7-88ec-0d02ba343ba5","order_by":2,"name":"Thomas Jensen","email":"","orcid":"https://orcid.org/0000-0002-2560-6784","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Jensen","suffix":""},{"id":462343793,"identity":"e1c7453e-0f3a-40cd-b335-cda14831d011","order_by":3,"name":"Kaiyu Zheng","email":"","orcid":"https://orcid.org/0000-0002-9002-6292","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Kaiyu","middleName":"","lastName":"Zheng","suffix":""}],"badges":[],"createdAt":"2025-02-19 18:30:16","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-6066377/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-6066377/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85566803,"identity":"74db3550-7765-4877-894c-1ecd278714db","added_by":"auto","created_at":"2025-06-27 14:48:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2049230,"visible":true,"origin":"","legend":"","description":"","filename":"Savtchenkoetalwfigs.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6066377/v2_covered_f0293197-daf7-4b52-b654-d19608cdbd33.pdf"},{"id":83839313,"identity":"0c55ea6c-5eb7-4511-8c9f-715feb3d192a","added_by":"auto","created_at":"2025-06-03 13:51:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":723536,"visible":true,"origin":"","legend":"Supplementary Figures","description":"","filename":"SupplementaryFigs.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6066377/v2/a411b5eb4e3dc09909b224ef.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Stochastic tissue environment expands spatial limits of synaptic and astrocytic glutamate actions","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6066377/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6066377/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The point precision of excitatory transmission relies on high-affinity astrocytic transporters that rapidly buffer glutamate escaping from the synaptic cleft. 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