The pathogenicity of the glutamate metabolic cycle in schizophrenia determined by hippocampal spectroscopic profiling

The pathogenicity of the glutamate metabolic cycle in schizophrenia determined by hippocampal spectroscopic profiling | 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 The pathogenicity of the glutamate metabolic cycle in schizophrenia determined by hippocampal spectroscopic profiling Scott Small, Jia Guo, Ragy Girgis, Sunil Goodwani, Michael Soth, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6050519/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 Hippocampal hyperactivity in schizophrenia is an early abnormality linked to its pathognomonic symptoms. An upregulation of the ‘glutamate metabolic cycle’, a pathway dedicated to maintaining normal synaptic excitability, is hypothesized to be pathogenic and to have therapeutic potential. Testing the hypothesis requires profiling the pathway’s three key metabolites -- glutamate, glutamine, and GABA. We begin by using a newly developed processing method capable of measuring these hippocampal metabolites via standard 1H-magnetic resonance spectroscopy (1H-MRS). We profiled the metabolites in patients with attenuated psychotic symptoms, a cohort enriched for early-stage schizophrenia and related psychotic disorders. More than just confirming abnormal pathway upregulation, the resultant profile isolated glutaminase 1 (GLS1) as the pathogenic driver. GLS1-dependent pathway upregulation was found to mechanistically underlie hippocampal hyperactivity and to associate with the illness’ symptoms. Next, to test the pathway’s therapeutic potential we used a newly developed 1H-MRS acquisition protocol optimized to measure the metabolites in mice. Hippocampal profiling GLS1 haploinsufficient mice showed that the pathway can be safely downregulated and identified a therapeutic goal. Profiling the effects of a GLS1 inhibiter that belongs to a drug family approved for clinical trials shows that the pathway can be pharmacologically targeted. Finally, profiling the effect of the inhibitor using the benchmark, ex-vivo mass spectrometry, validates that the new 1H-MRS tools are reliable biomarkers. Collectively, our findings can accelerate drug development for an illness that first strikes the hippocampus of young people before pathologically progressing and resulting in lifelong morbidity. Health sciences/Diseases/Psychiatric disorders/Schizophrenia Health sciences/Medical research/Biomarkers Full Text Additional Declarations Yes there is potential Competing Interest. Author Scott A. Small is a scientific co-founder of Retromer Therapeutics. 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-6050519","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":449315277,"identity":"01b6e80e-babe-4a67-b934-49cc180fb338","order_by":0,"name":"Scott Small","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYHACxgcfKhgY+BgY2BgSQPwDhLUwG844A1JPghY2Yd42qBYGYrTItx9/xjhznp0cm0R22oMHNQxyfDcS8GsxOJNj9uDjtmRjNonc7QYJxxiMJQlqYchhN5y57UBim0TuNokENobEDYS0yPc/fybNOwem5R9DPUEtDDcSzKR5G6BaEtsYEgwIOuzGG2PDGceAfuF5u90gsU/CcOaZB4Qclv7wwYcaOzl+9txtD398s5HnO07IYWhAgjTlo2AUjIJRMAqwAwAj0UaNb10AFAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-4777-1502","institution":"Columbia University","correspondingAuthor":true,"prefix":"","firstName":"Scott","middleName":"","lastName":"Small","suffix":""},{"id":449315278,"identity":"4778ffdd-22a8-43f8-b413-30ea55b97118","order_by":1,"name":"Jia Guo","email":"","orcid":"https://orcid.org/0000-0003-4803-0279","institution":"Columbia University","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Guo","suffix":""},{"id":449315279,"identity":"fa5a827d-0b7a-46c5-8136-3ce2d788aa7b","order_by":2,"name":"Ragy Girgis","email":"","orcid":"","institution":"Columbia University","correspondingAuthor":false,"prefix":"","firstName":"Ragy","middleName":"","lastName":"Girgis","suffix":""},{"id":449315280,"identity":"59bf5bb6-1911-46e6-977c-efeba8fb7eef","order_by":3,"name":"Sunil Goodwani","email":"","orcid":"","institution":"University of Texas MD Anderson Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Sunil","middleName":"","lastName":"Goodwani","suffix":""},{"id":449315281,"identity":"bd6ddab4-f261-445a-80ad-d1f2f39ed9a3","order_by":4,"name":"Michael Soth","email":"","orcid":"","institution":"The University of Texas MD Anderson Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Soth","suffix":""},{"id":449315282,"identity":"dbcec7f9-5cc3-4776-aba9-dbdcf6e2cee9","order_by":5,"name":"Christopher Wu","email":"","orcid":"","institution":"Columbia University","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Wu","suffix":""},{"id":449315283,"identity":"803d4db3-835e-4cfe-aefd-6882e6248ae4","order_by":6,"name":"Stephen Rayport","email":"","orcid":"","institution":"Columbia University","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Rayport","suffix":""},{"id":449315284,"identity":"480714e1-8933-4205-a35c-9abcface37f3","order_by":7,"name":"William Ray","email":"","orcid":"https://orcid.org/0000-0002-4491-167X","institution":"The University of Texas MD Anderson Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"Ray","suffix":""},{"id":449315285,"identity":"220c76d2-e5fc-4267-b3f4-b28b3a88678e","order_by":8,"name":"Douglas Rothman","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Douglas","middleName":"","lastName":"Rothman","suffix":""}],"badges":[],"createdAt":"2025-02-17 19:15:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6050519/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6050519/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84828340,"identity":"0193b9d8-1c65-42ac-b3a0-d3f91be3f10f","added_by":"auto","created_at":"2025-06-17 17:53:20","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1302779,"visible":true,"origin":"","legend":"Article File","description":"","filename":"gmcpaperfebruary17.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6050519/v1_covered_82dac008-2171-499d-91ee-767e297d2d46.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nAuthor Scott A. Small is a scientific co-founder of Retromer Therapeutics.","formattedTitle":"The pathogenicity of the glutamate metabolic cycle in schizophrenia determined by hippocampal spectroscopic profiling","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-6050519/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6050519/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Hippocampal hyperactivity in schizophrenia is an early abnormality linked to its pathognomonic symptoms. An upregulation of the ‘glutamate metabolic cycle’, a pathway dedicated to maintaining normal synaptic excitability, is hypothesized to be pathogenic and to have therapeutic potential. Testing the hypothesis requires profiling the pathway’s three key metabolites -- glutamate, glutamine, and GABA. We begin by using a newly developed processing method capable of measuring these hippocampal metabolites via standard 1H-magnetic resonance spectroscopy (1H-MRS). We profiled the metabolites in patients with attenuated psychotic symptoms, a cohort enriched for early-stage schizophrenia and related psychotic disorders. More than just confirming abnormal pathway upregulation, the resultant profile isolated glutaminase 1 (GLS1) as the pathogenic driver. GLS1-dependent pathway upregulation was found to mechanistically underlie hippocampal hyperactivity and to associate with the illness’ symptoms. Next, to test the pathway’s therapeutic potential we used a newly developed 1H-MRS acquisition protocol optimized to measure the metabolites in mice. Hippocampal profiling GLS1 haploinsufficient mice showed that the pathway can be safely downregulated and identified a therapeutic goal. Profiling the effects of a GLS1 inhibiter that belongs to a drug family approved for clinical trials shows that the pathway can be pharmacologically targeted. Finally, profiling the effect of the inhibitor using the benchmark, ex-vivo mass spectrometry, validates that the new 1H-MRS tools are reliable biomarkers. 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