Short-Term Synaptic Plasticity Modulates the Outcome of Neurodegenerative Diseases

Short-Term Synaptic Plasticity Modulates the Outcome of Neurodegenerative Diseases | 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 Research Article Short-Term Synaptic Plasticity Modulates the Outcome of Neurodegenerative Diseases Han ZHANG, Yusuf MOHIDEEN, Chi Chung Alan FUNG This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9196722/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Alzheimer's disease (AD) is characterised by progressive neuronal loss and synaptic dysfunction that disrupt memory-encoding neural circuits. Short-term synaptic plasticity (STP), which governs transient activity-dependent changes in synaptic efficacy on millisecond-to-second timescales, represents a potentially targetable mechanism for dynamically compensating circuit-level deficits without requiring structural repair. Using the NEST Simulator, we constructed a spiking neural network of 1,000 Hodgkin--Huxley excitatory and 250 leaky integrate-and-fire inhibitory neurons with embedded memory engram assemblies, modelling AD pathology through accelerated neuronal loss and pathological hyperexcitability. Synaptic dynamics were governed by the Tsodyks--Markram model, and compensatory interventions were evaluated by systematically sweeping the facilitation time constant \((\tau_{\text{fac}})\) and recovery time constant \((\tau_{\text{rec}})\) across a two-dimensional parameter space. Engram recall fidelity was quantified by the selectivity ratio \((\Gamma)\) , and network-level oscillatory dynamics were assessed via simulated Local Field Potential power spectral density. Increasing \((\tau_{\text{fac}})\) from 500\,ms to 1,250\,ms rescued engram selectivity in the AD model at intermediate synaptic weight regimes inaccessible at baseline, and partially or fully restored theta- and alpha-band LFP power respectively. The \((\tau_{\text{rec}})\) sweep revealed a fundamental trade-off: increasing \((\tau_{\text{rec}})\) suppressed pathological hyperexcitability, whereas decreasing it maximised \((\Gamma)\) , with the two objectives requiring opposing parameter changes. These results demonstrate that STF and STD modulation exert mechanistically distinct compensatory effects, and identify bounded therapeutic windows within which dynamic re-tuning of surviving synaptic circuits can meaningfully mitigate AD-related functional deficits. Alzheimer's disease short-term synaptic plasticity computational neuroscience neural network modeling Tsodyks-Markram model Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted 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. 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-9196722","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":620513871,"identity":"579a6a82-6db6-46da-9c2f-4c1768c94040","order_by":0,"name":"Han ZHANG","email":"","orcid":"","institution":"CityU Shenzhen Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"ZHANG","suffix":""},{"id":620513877,"identity":"4adf7ed4-622f-4d71-b2f3-0c1ce04f6ca1","order_by":1,"name":"Yusuf MOHIDEEN","email":"","orcid":"","institution":"City University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Yusuf","middleName":"","lastName":"MOHIDEEN","suffix":""},{"id":620513891,"identity":"fcfd0b53-7faf-4fae-8f01-b440508aa634","order_by":2,"name":"Chi Chung Alan FUNG","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDACdhBhA2I0MByACCUwMMOYWAEziEgDYp4DDAcOkKZFIoGBgSgt/M3Mzx4wJBzOk498/PDwx7bDDPzsOQbMBWdwa5E4zGZuANRSbHg7zeDAQaAWyZ43BswzbuBx2GEGMwnGH4cTN87OYQBrMbgBtIXnA24d8ofZv0kAbUncOPMMRIs9IS0Gh3nMwFrmS/BAbZEAacHjMMPDPGUSCQnpiRt4gH45cy6dR+LMs4LDPHi8L3e8fZvEhwTrxPnthx9/qCizluNvT974mOcYHu+DQALIhQeABCMbAw9I4AABDRAg3wAi/xCldhSMglEwCkYYAAARzVe3qy0QJAAAAABJRU5ErkJggg==","orcid":"","institution":"City University of Hong Kong","correspondingAuthor":true,"prefix":"","firstName":"Chi","middleName":"Chung Alan","lastName":"FUNG","suffix":""}],"badges":[],"createdAt":"2026-03-23 07:10:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9196722/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9196722/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107484256,"identity":"e917a552-75f9-4419-84bf-f5e11e70ec59","added_by":"auto","created_at":"2026-04-22 02:31:16","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1977720,"visible":true,"origin":"","legend":"","description":"","filename":"submit.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9196722/v1_covered_103cb682-9a3f-4676-aa6a-b1b3aa319d36.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Short-Term Synaptic Plasticity Modulates the Outcome of Neurodegenerative Diseases","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Alzheimer's disease, short-term synaptic plasticity, computational neuroscience, neural network modeling, Tsodyks-Markram model","lastPublishedDoi":"10.21203/rs.3.rs-9196722/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9196722/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAlzheimer's disease (AD) is characterised by progressive neuronal loss and synaptic dysfunction that disrupt memory-encoding neural circuits. Short-term synaptic plasticity (STP), which governs transient activity-dependent changes in synaptic efficacy on millisecond-to-second timescales, represents a potentially targetable mechanism for dynamically compensating circuit-level deficits without requiring structural repair. Using the NEST Simulator, we constructed a spiking neural network of 1,000 Hodgkin--Huxley excitatory and 250 leaky integrate-and-fire inhibitory neurons with embedded memory engram assemblies, modelling AD pathology through accelerated neuronal loss and pathological hyperexcitability. Synaptic dynamics were governed by the Tsodyks--Markram model, and compensatory interventions were evaluated by systematically sweeping the facilitation time constant \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\((\\tau_{\\text{fac}})\\)\u003c/span\u003e\u003c/span\u003e and recovery time constant \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\((\\tau_{\\text{rec}})\\)\u003c/span\u003e\u003c/span\u003e across a two-dimensional parameter space. Engram recall fidelity was quantified by the selectivity ratio \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\((\\Gamma)\\)\u003c/span\u003e\u003c/span\u003e, and network-level oscillatory dynamics were assessed via simulated Local Field Potential power spectral density. Increasing \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\((\\tau_{\\text{fac}})\\)\u003c/span\u003e\u003c/span\u003e from 500\\,ms to 1,250\\,ms rescued engram selectivity in the AD model at intermediate synaptic weight regimes inaccessible at baseline, and partially or fully restored theta- and alpha-band LFP power respectively. The \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\((\\tau_{\\text{rec}})\\)\u003c/span\u003e\u003c/span\u003e sweep revealed a fundamental trade-off: increasing \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\((\\tau_{\\text{rec}})\\)\u003c/span\u003e\u003c/span\u003e suppressed pathological hyperexcitability, whereas decreasing it maximised \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\((\\Gamma)\\)\u003c/span\u003e\u003c/span\u003e, with the two objectives requiring opposing parameter changes. These results demonstrate that STF and STD modulation exert mechanistically distinct compensatory effects, and identify bounded therapeutic windows within which dynamic re-tuning of surviving synaptic circuits can meaningfully mitigate AD-related functional deficits.\u003c/p\u003e","manuscriptTitle":"Short-Term Synaptic Plasticity Modulates the Outcome of Neurodegenerative Diseases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-10 03:47:26","doi":"10.21203/rs.3.rs-9196722/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","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}}],"origin":"","ownerIdentity":"94be91c0-82cc-4d60-bede-ebd67e410935","owner":[],"postedDate":"April 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-19T01:23:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-10 03:47:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9196722","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9196722","identity":"rs-9196722","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}