CINXE.COM

<!DOCTYPE html>      <html lang='en' class='no-js'>  <head> <meta charset='utf-8'> <meta content='text/html; charset=UTF-8' http-equiv='Content-Type'> <meta content='The Journal of Clinical Investigation' name='AUTHOR'>  <meta content='width=device-width, initial-scale=1.0' name='viewport'> <link href='/rss' rel='alternate' title='JCI New Article RSS' type='application/rss+xml'> <meta name="csrf-param" content="authenticity_token" /> <meta name="csrf-token" content="dKgdS2+sspXwB6pFwpK4S59XB6JsuVqjf4jwY+1f0JMNYWmfFFfInAshYq0T3ZlW74pxr93dmpR6ezoN5p1XTw==" /> <link rel="shortcut icon" type="image/x-icon" href="/assets/jci-favicon-378ea4dd43f03bc78136c6a261d9b28f6811fe59d12db426eae78cf0691b0008.ico" /> <title> JCI - Welcome </title> <link rel="stylesheet" media="all" href="/assets/application-4e3473ed7442aa1dc35d11f58ed4edfbd690fa57a3eb3a1daca0cd68dc7fb1e0.css" />  <style> @font-face { font-family: "klavika-bold"; src: url("///var/www/jci/jci/releases/20250404161853/vendor/common/fonts/klavika/eot/KlavikaWebBasicBold.eot") format('eot'), src: url("///var/www/jci/jci/releases/20250404161853/vendor/common/fonts/klavika/eot/KlavikaWebBasicBold.eot?#iefix") format("embedded-opentype"), url("///var/www/jci/jci/releases/20250404161853/vendor/common/fonts/klavika/woff/KlavikaWebBasicBold.woff") format("woff") } </style> <script> //Google Tag Manager Data Layer //Values must be set before GTM tags are triggered window.dataLayer = window.dataLayer || []; window.dataLayer.push({ 'siteName': 'content-jci', 'ipAddress': '8.222.208.146', 'environment': 'production', }); </script> <script src="/assets/vendor/modernizr-2f68aa04c7424c280c5bc9db8b68f7f6ff70bcd38254c5b89383eac8e89b1781.js"></script> <script type='text/javascript'> var googletag = googletag || {}; googletag.cmd = googletag.cmd || []; (function () { var gads = document.createElement('script'); gads.async = true; gads.type = 'text/javascript'; var useSSL = 'https:' == document.location.protocol; gads.src = (useSSL ? 'https:' : 'http:') + '//www.googletagservices.com/tag/js/gpt.js'; var node = document.getElementsByTagName('script')[0]; node.parentNode.insertBefore(gads, node); })(); googletag.cmd.push(function () { // NOTE: This script manages google ads, more info at doc/GoogleAds.md var mapping = googletag.sizeMapping().addSize([800, 600], [300, 250]).addSize([640, 480], [260, 217]).build(); var mapping2 = googletag.sizeMapping() .addSize([1920, 1080], [728, 90])//All desktop like resolutions are set to 728x90 .addSize([800, 600], [728, 90]) .addSize([640, 480], [728, 90]) .addSize([0, 0], [320, 50]) //Smaller than 640x480 screens .build(); googletag.defineSlot('/82117132/jci-homepage-med-rectangle-left-col-top', [[300, 250],[260, 217]], 'jci-homepage-med-rectangle-left-col-top').defineSizeMapping(mapping).addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-article-interior-leaderboard-top', [[728, 90],[320, 50]], 'jci-article-interior-leaderboard-top').defineSizeMapping(mapping2).addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-article-interior-leaderboard-bottom', [728, 90], 'jci-article-interior-leaderboard-bottom').addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-article-interior-skyscraper-right-col', [160, 600], 'jci-article-interior-skyscraper-right-col').addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-interior-skyscraper-right-col', [160, 600], 'jci-interior-skyscraper-right-col').addService(googletag.pubads()); // collapseEmptyDivs requires all slots be defined above. googletag.pubads().collapseEmptyDivs(true); googletag.enableServices(); }); </script> </head> <body class='' id='tags_controller'> <div class='off-canvas-wrap' data-offcanvas=''> <div class='inner-wrap'> <div class='fixed show-for-large-up'> <div class='row menu-align' id='logo-bar'> <div class='small-12 columns'> <div class='cross-journal-container'> Go to <a href='http://insight.jci.org'>JCI Insight</a> </div> <a href="/"><img src="/assets/common/jci-spelled-out-white-on-transparent.20160208-958617d51a205b239bcef41eae5703962aee0ae2fcc9fbda0237e635a09ac7f3.png" /></a> </div> </div> <div class='row menu-align' id='journal-bar'> <div class='small-12 columns'> <ul class='inline-list'> <li><a href="/kiosks/about">About</a></li> <li><a href="/kiosks/editorial-board">Editors</a></li> <li><a href="/kiosks/about/consulting-editors">Consulting Editors</a></li> <li><a href="/kiosks/authors">For authors</a></li> <li><a href="/kiosks/ethics">Publication ethics</a></li> <li><a href="/kiosks/connect">Publication alerts by email</a></li> <li><a href="/kiosks/advertise">Advertising</a></li> <li><a href="https://the-asci.org/controllers/asci/JobBoard.php">Job board</a></li> <li><a href="/kiosks/contact">Contact</a></li> </ul> </div> </div> <div id='content-bar'> <nav class='top-bar' data-topbar=''> <section class='top-bar-section'> <ul class='left'> <li class='not-click'> <a href="/tags/141">Clinical Research and Public Health</a> </li> <li class='not-click'> <a id="topmenu_current_issue" href="/current">Current issue</a> </li> <li class='not-click'> <a href="/archive">Past issues</a> </li> <li class='has-dropdown not-click'> <a>By specialty</a> <ul class='dropdown'> <li><a href="/tags/118">COVID-19</a></li> <li><a href="/tags/15">Cardiology</a></li> <li><a href="/tags/21">Gastroenterology</a></li> <li><a href="/tags/25">Immunology</a></li> <li><a href="/tags/28">Metabolism</a></li> <li><a href="/tags/31">Nephrology</a></li> <li><a href="/tags/32">Neuroscience</a></li> <li><a href="/tags/33">Oncology</a></li> <li><a href="/tags/36">Pulmonology</a></li> <li><a href="/tags/42">Vascular biology</a></li> <li><a href="/specialties">All ...</a></li> </ul> </li> <li class='has-dropdown not-click'> <a href="/videos">Videos</a> <ul class='dropdown'> <li><a href="/videos/cgms">Conversations with Giants in Medicine</a></li> <li><a href="/videos/video_abstracts">Video Abstracts</a></li> </ul> </li> <li class='has-dropdown not-click'> <a href="/tags/reviews">Reviews</a> <ul class='dropdown'> <li> <label>Reviews</label> </li> <li><a href="/tags/reviews">View all reviews ...</a></li> <li class='divider'></li> <li> <label>Review Series</label> </li> <li><a href="/review_series/131">Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)</a></li> <li><a href="/review_series/130">Microbiome in Health and Disease (Feb 2025)</a></li> <li><a href="/review_series/127">Substance Use Disorders (Oct 2024)</a></li> <li><a href="/review_series/128">Clonal Hematopoiesis (Oct 2024)</a></li> <li><a href="/review_series/129">Sex Differences in Medicine (Sep 2024)</a></li> <li><a href="/review_series/126">Vascular Malformations (Apr 2024)</a></li> <li><a href="/review_series/125">Lung inflammatory injury and tissue repair (Jul 2023)</a></li> <li> <a href="/review_series">View all review series ...</a> </li> </ul> </li> <li class='not-click'> <a href="/tags/111">Viewpoint</a> </li> <li class='has-dropdown not-click'> <a>Collections</a> <ul class='dropdown'> <li><a href="/in-press-preview">In-Press Preview</a></li> <li><a href="/tags/141">Clinical Research and Public Health</a></li> <li><a href="/tags/127">Research Letters</a></li> <li><a href="/tags/75">Letters to the Editor</a></li> <li><a href="/tags/56">Editorials</a></li> <li><a href="/tags/44">Commentaries</a></li> <li><a href="/tags/123">Editor's notes</a></li> <li><a href="/tags/2">Reviews</a></li> <li><a href="/tags/111">Viewpoints</a></li> <li><a href="/collections/topic/jci-100th-anniversary">100th anniversary</a></li> <li><a href="/top_articles">Top read articles</a></li> </ul> </li> </ul> <ul class='right'> <li class='has-form'> <div id='search-area'> <form action="/search/results" accept-charset="UTF-8" method="get"> <input type="text" name="q" id="q" value="" placeholder="Search the JCI" /> <input type="image" src="/assets/search-black-ba9b554d6f74b1c93d6e6ab71d1c9830c18a20fc6b7e72393f136f5d875141ac.png" value="" /> </form> </div> </li> </ul> </section> </nav> </div> </div> <nav class='tab-bar hide-for-large-up fixed' id='small-navbar'> <section class='left-small'> <a class='left-off-canvas-toggle menu-icon'> <span></span> </a> </section> <section class='middle tab-bar-section'> <h1 class='title'><a href="/"><img width="40" src="/assets/common/jci-only-white-6c989e8f9744a714482158b82319d50aa8437aa4c8524c4f3dcf8450299cd4b7.png" /></a></h1> </section> </nav> <aside class='left-off-canvas-menu'> <ul class='off-canvas-list'> <li> <label>The Journal of Clinical Investigation</label> </li> <li><form action="/search/results" accept-charset="UTF-8" method="get"> <div class='row collapse' id='search-div-offcanvas'> <div class='small-8 columns'> <input name='q' placeholder='Search the JCI' type='text'> </div> <div class='small-4 columns'> <input type="image" src="/assets/common/search-white-530f3f95b9080d73eba51eaeffdf1a3922af42ccc277a2d1d987b8aa24423c96.png" id="search-icon-offcanvas" /> </div> </div> </form> </li> <li><a id="offcanvas_current_issue" href="/current">Current issue</a></li> <li><a href="/archive">Past issues</a></li> <li><a href="/specialties">Specialties</a></li> <li><a href="/tags/reviews">Reviews</a></li> <li><a href="/review_series">Review series</a></li> <li> <label>Videos</label> </li> <li><a href="/videos/cgms">Conversations with Giants in Medicine</a></li> <li><a href="/videos/video_abstracts">Video Abstracts</a></li> <li> <label>Collections</label> </li> <li><a href="/in-press-preview">In-Press Preview</a></li> <li><a href="/tags/141">Clinical Research and Public Health</a></li> <li><a href="/tags/127">Research Letters</a></li> <li><a href="/tags/75">Letters to the Editor</a></li> <li><a href="/tags/56">Editorials</a></li> <li><a href="/tags/44">Commentaries</a></li> <li><a href="/tags/123">Editor's notes</a></li> <li><a href="/tags/2">Reviews</a></li> <li><a href="/tags/111">Viewpoints</a></li> <li><a href="/collections/topic/jci-100th-anniversary">100th anniversary</a></li> <li><a href="/top_articles">Top read articles</a></li> <li> <label>Journal Details</label> </li> <li><a href="/kiosks/about">About</a></li> <li><a href="/kiosks/editorial-board">Editors</a></li> <li><a href="/kiosks/about/consulting-editors">Consulting Editors</a></li> <li><a href="/kiosks/authors">For authors</a></li> <li><a href="/kiosks/ethics">Publication ethics</a></li> <li><a href="/kiosks/connect">Publication alerts by email</a></li> <li><a href="/kiosks/advertise">Advertising</a></li> <li><a href="https://the-asci.org/controllers/asci/JobBoard.php">Job board</a></li> <li><a href="/kiosks/contact">Contact</a></li> </ul> </aside> <a class='exit-off-canvas'></a>  <div class='row content-wrapper'> <div class='small-12 columns'> <div class='menu-align'> <div class='row'> <div class='large-10 medium-9 small-12 columns'> <h3>Neuroscience</h3> <div class='row'> <div class='small-10 medium-7 large-5 small-centered columns'> <ul class='tabs row' data-tab> <li class='tab-title small-6 centered active'> <a href='#articles'>625 Articles</a> </li> <li class='tab-title small-6 centered '> <a href='#posts'>7 Posts</a> </li> </ul> </div> </div> <div class='tabs-content'> <div class='content active' id='articles'> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/32?content=articles&page=2">2</a></li> <li><a href="/tags/32?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/32?content=articles&page=62">62</a></li> <li><a href="/tags/32?content=articles&page=63">63</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/32?content=articles&page=2">Next →</a></li></ul></div> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186432">Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186432">Joie Lin, … , John R. Yates III, Christina J. Sigurdson</a> <a class='hide-for-small show-more' data-reveal-id='article45951-more' href='#'> <div class='article-authors'> Joie Lin, … , John R. Yates III, Christina J. Sigurdson </div> </a> <span class='article-published-at'> Published April 4, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186432">https://doi.org/10.1172/JCI186432</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186432">Text</a> | <a href="/articles/view/186432/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186432' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45951-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186432">Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186432">Text</a></li> <li><a class="button tiny" href="/articles/view/186432/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Neuronal hyperexcitability precedes synapse loss in certain neurodegenerative diseases, yet the synaptic membrane interactions and downstream signaling events remain unclear. The disordered amino terminus of the prion protein (PrPC) has been implicated in aberrant signaling in prion and Alzheimer’s disease. To disrupt neuronal interactions and signaling linked to the amino terminus, here we CRISPR-engineered a knock-in mouse expressing mutant PrPC (G92N), generating an N-linked glycosylation site between two functional motifs. Mice developed seizures and necrosis of hippocampal pyramidal neurons, similar to prion-infected mice and consistent with excitotoxicity. Phosphoproteomics revealed phosphorylated glutamate receptors and calcium-sensitive kinases, including protein kinase C (PKC). Additionally, 92N-PrPC-expressing neurons show persistent calcium influx as well as dendritic beading, which was rescued by an NMDA receptor antagonist. Finally, survival of Prnp92N mice was prolonged by blocking active NMDA receptor channels. We propose dysregulated PrPC – NMDA receptor - induced signaling can trigger excitatory – inhibitory imbalance, spongiform degeneration, and neurotoxicity, and that calcium dysregulation is central to PrPC-linked neurodegeneration.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Joie Lin, Julia A. Callender, Joshua E. Mayfield, Daniel B. McClatchy, Daniel Ojeda-Juárez, Mahsa Pourhamzeh, Katrin Soldau, Timothy D. Kurt, Garrett A. Danque, Helen K. Khuu, Josephina E. Ronson, Donald P. Pizzo, Yixing Du, Maxwell A. Gruber, Alejandro M. Sevillano, Jin Wang, Christina D. Orrú, Joy Chen, Gail Funk, Patricia Aguilar-Calvo, Brent D. Aulston, Subhojit Roy, Jong M. Rho, Jack D. Bui, Alexandra C. Newton, Stuart A. Lipton, Byron Caughey, Gentry N. Patrick, Kim Doré, John R. Yates III, Christina J. Sigurdson</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179881">Prefrontal correlates of fear generalization during endocannabinoid depletion</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/179881">Luis E. Rosas-Vidal, … , Markus Heilig, Sachin Patel</a> <a class='hide-for-small show-more' data-reveal-id='article45894-more' href='#'> <div class='article-authors'> Luis E. Rosas-Vidal, … , Markus Heilig, Sachin Patel </div> </a> <span class='article-published-at'> Published March 27, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI179881">https://doi.org/10.1172/JCI179881</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179881">Text</a> | <a href="/articles/view/179881/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179881' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45894-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179881">Prefrontal correlates of fear generalization during endocannabinoid depletion</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179881">Text</a></li> <li><a class="button tiny" href="/articles/view/179881/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation but its role in balancing fear discrimination versus generalization is not known. To address this, we used a combination of plasma endocannabinoid measurement and neuroimaging from a childhood maltreatment-exposed and non-exposed mixed population combined with human and rodent fear conditioning models. Here we show that 2-AG levels are inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increases the proportion of neurons, and the similarity between neuronal representations, of threat-predictive and neutral stimuli within prelimbic prefrontal cortex neuronal ensembles. In humans, increased dorsolateral prefrontal cortical-amygdala resting state connectivity is inversely correlated with fear generalization. These data provide convergent cross-species evidence that 2-AG is a key regulator of fear generalization and further support the notion that 2-AG deficiency could represent a trauma-related disorder susceptibility endophenotype.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Luis E. Rosas-Vidal, Saptarnab Naskar, Leah M. Mayo, Irene Perini, Rameen Masroor, Megan Altemus, Liorimar Ramos-Medina, S. Danyal Zaidi, Hilda Engelbrektsson, Puja Jagasia, Markus Heilig, Sachin Patel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/188314">Glucagon-like peptide-1 receptor agonists but not dipeptidyl peptidase-4 inhibitors reduce alcohol intake</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188314">Mehdi Farokhnia, … , Christopher T. Rentsch, Lorenzo Leggio</a> <a class='hide-for-small show-more' data-reveal-id='article45838-more' href='#'> <div class='article-authors'> Mehdi Farokhnia, … , Christopher T. Rentsch, Lorenzo Leggio </div> </a> <span class='article-published-at'> Published March 6, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI188314">https://doi.org/10.1172/JCI188314</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188314">Text</a> | <a href="/articles/view/188314/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188314' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45838-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188314">Glucagon-like peptide-1 receptor agonists but not dipeptidyl peptidase-4 inhibitors reduce alcohol intake</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188314">Text</a></li> <li><a class="button tiny" href="/articles/view/188314/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Background: Despite growing preclinical evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be repurposed to treat alcohol use disorder (AUD), clinical evidence is scarce. Additionally, the potential impact of dipeptidyl peptidase-4 inhibitors (DPP-4Is) on alcohol intake is largely unknown. Methods: We conducted a large cohort study using 2008-2023 electronic health records data from the U.S. Department of Veterans Affairs. Changes in Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores were compared between propensity-score-matched GLP-1RA recipients, DPP-4I recipients, and unexposed comparators. We further tested the effects of two DPP-4Is, linagliptin and omarigliptin, on binge-like alcohol drinking in mice and operant oral alcohol self-administration in alcohol-dependent rats, models previously used to show a significant effect of the GLP-1RA semaglutide in reducing alcohol intake. Results: GLP-1RA recipients reported a greater reduction in AUDIT-C scores than unexposed individuals [difference-in-difference: 0.09(0.03,0.14), p=0.0025] and DPP-4I recipients [difference-in-difference: 0.11(0.05,0.17), p=0.0002]. Reductions in drinking were more pronounced among individuals with baseline AUD [GLP-1RA vs. unexposed: 0.51(0.29,0.72), p<0.0001; GLP-1RA vs. DPP-4I: 0.65(0.43,0.88), p<0.0001] and baseline hazardous drinking [GLP-1RA vs. unexposed: 1.38(1.07,1.69), p<0.0001; GLP-1RA vs. DPP-4I: 1.00(0.68,1.33), p<0.0001]. There were no differences between DPP-4I recipients and unexposed individuals. The latter results were confirmed via a reverse translational approach. Specifically, neither linagliptin nor omarigliptin reduced alcohol drinking in mice or rats. The rodent experiments also confirmed target engagement as both DPP-4Is reduced blood glucose levels. Conclusion: Convergent findings across humans, mice, and rats indicate that GLP-1RAs but not DPP-4Is reduce alcohol consumption and may be efficacious in treating AUD.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Mehdi Farokhnia, John Tazare, Claire L. Pince, Nicolaus Bruns Vi, Joshua C. Gray, Vincent Lo Re III, David A. Fiellin, Henry R. Kranzler, George F. Koob, Amy C. Justice, Leandro F. Vendruscolo, Christopher T. Rentsch, Lorenzo Leggio</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/171948">Patterns of autoantibody expression in multiple sclerosis identified through development of an autoantigen discovery technology</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/171948">Europe B. DiCillo, … , David Pisetsky, Thomas Tedder</a> <a class='hide-for-small show-more' data-reveal-id='article45805-more' href='#'> <div class='article-authors'> Europe B. DiCillo, … , David Pisetsky, Thomas Tedder </div> </a> <span class='article-published-at'> Published March 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/5">135(5)</a>:e171948. <a href="https://doi.org/10.1172/JCI171948">https://doi.org/10.1172/JCI171948</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/171948">Text</a> | <a href="/articles/view/171948/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI171948' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/171948/figure/1' ref='group' title='Genome-wide protein fragment expression library generation. (A) Expression library construction. mRNA purified from HEp-2 cells, astrocytes, brain white matter, and PBMCs was fragmented to generate ORF transcripts encoding domain-sized protein fragments. > 1 × 106 distinct in-frame transcripts were cloned for phage library construction. Individual libraries were proportionally pooled. (B) Library cDNA insert size distributions. Histograms show cDNA insert sizes (base pairs) of the 4 final expression libraries. (C) Sequencing count values (log10 scale, y-axis) represent the relative number of annotated genes in each library. The x-axis shows ranking of each gene from highest counts to lowest counts relative to each library. (D) Venn diagram showing the number of unique proteins each cell type contributes to the total transcript library. (E) Representative protein fragments of the ACTB gene expressed within the pooled cDNA library after selection. Black lines represent expressed library protein fragments of the ACTB protein. The 112 fragments shown represent 2,554 total ACTB fragments in the library.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/171000/171948/small/JCI171948.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45805-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/171948">Patterns of autoantibody expression in multiple sclerosis identified through development of an autoantigen discovery technology</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/171948">Text</a></li> <li><a class="button tiny" href="/articles/view/171948/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Multiple sclerosis (MS) is a debilitating autoimmune disease of the CNS, which is characterized by demyelination and axonal injury and frequently preceded by a demyelinating event called clinically isolated syndrome (CIS). Despite the importance of B cells and autoantibodies in MS pathology, their target specificities remain largely unknown. For an agnostic and comprehensive evaluation of autoantibodies in MS, we developed and employed what we believe to be a novel autoantigen discovery technology, the Antigenome Platform. This Platform is a high-throughput assay comprising large-fragment (approximately 100 amino acids) cDNA libraries, phage display, serum antibody screening technology, and robust bioinformatics analysis pipelines. For autoantibody discovery, we assayed serum samples from CIS patients who received either placebo or treatment who were enrolled in the REFLEX clinical trial, which assessed the effects of IFN-β-1a (Rebif) clinical and MRI activity in patients with CIS. Serum autoantibodies from patients with CIS were significantly and reproducibly enriched for known and previously unreported protein targets; 166 targets were selected by over 10% of patients’ sera. Further, 10 autoantibody biomarkers associated with disease activity and 17 associated with patient response to IFN-β-1a therapy. These findings indicate widespread autoantibody production in MS and provide biomarkers for continued study and prediction of disease progression.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Europe B. DiCillo, Evgueni Kountikov, Minghua Zhu, Stefan Lanker, Danielle E. Harlow, Elizabeth R. Piette, Weiguo Zhang, Brooke Hayward, Joshua Heuler, Julie Korich, Jeffrey L. Bennett, David Pisetsky, Thomas Tedder</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/188942">Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188942">Qianqian Ge, … , Li Shen, Jiadong Chen</a> <a class='hide-for-small show-more' data-reveal-id='article45813-more' href='#'> <div class='article-authors'> Qianqian Ge, … , Li Shen, Jiadong Chen </div> </a> <span class='article-published-at'> Published March 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/5">135(5)</a>:e188942. <a href="https://doi.org/10.1172/JCI188942">https://doi.org/10.1172/JCI188942</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188942">Text</a> | <a href="/articles/view/188942/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188942' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/188942/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/188000/188942/small/JCI188942.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45813-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188942">Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188942">Text</a></li> <li><a class="button tiny" href="/articles/view/188942/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult to determine the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA-seq approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2, and NFKBIA, which associate with mTOR pathway, inflammatory response, and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, γ-H2AX, and β-Gal, and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of patients with drug-resistant epilepsy with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent marker expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and what we believe to be new insights into the pathophysiological mechanisms of drug-resistant epilepsy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Qianqian Ge, Jiachao Yang, Fei Huang, Xinyue Dai, Chao Chen, Jingxin Guo, Mi Wang, Mengyue Zhu, Yijie Shao, Yuxian Xia, Yu Zhou, Jieqiao Peng, Suixin Deng, Jiachen Shi, Yiqi Hu, Huiying Zhang, Yi Wang, Xiaoqun Wang, Xiao-Ming Li, Zhong Chen, Yousheng Shu, Jun-Ming Zhu, Jianmin Zhang, Ying Shen, Shumin Duan, Shengjin Xu, Li Shen, Jiadong Chen</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185463">A multi-analyte blood test for acute spinal cord injury</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185463">Tej D. Azad, … , Nicholas Theodore, Chetan Bettegowda</a> <a class='hide-for-small show-more' data-reveal-id='article45828-more' href='#'> <div class='article-authors'> Tej D. Azad, … , Nicholas Theodore, Chetan Bettegowda </div> </a> <span class='article-published-at'> Published March 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/5">135(5)</a>:e185463. <a href="https://doi.org/10.1172/JCI185463">https://doi.org/10.1172/JCI185463</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185463">Text</a> | <a href="/articles/view/185463/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185463' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185463/figure/1' ref='group' title='Overview of study for detection of acute SCI via a multi-analyte assay of peripheral blood.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185463/small/JCI185463.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45828-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185463">A multi-analyte blood test for acute spinal cord injury</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185463">Text</a></li> <li><a class="button tiny" href="/articles/view/185463/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND Rapid diagnosis to facilitate urgent intervention is critical for treatment of acute spinal cord injury (SCI). We hypothesized that a multi-analyte blood biomarker would support point-of-care SCI diagnosis, correlate with injury severity, and predict long-term neurologic outcomes.METHODS Droplet digital PCR (ddPCR) assays were designed to amplify differentially hypomethylated genomic loci in spinal cord tissue. An optimized ddPCR assay was applied to cell-free DNA (cfDNA) from plasma samples collected from prospectively enrolled acute SCI patients. Targeted proteomic profiling was also performed. Spinal cord–derived cfDNA and plasma proteins were tested for their association with SCI and ability to predict conversion in American Spinal Injury Association (ASIA) score at 6 months.RESULTS A bespoke ddPCR assay detected spinal cord–derived cfDNA in plasma of 50 patients with acute SCI (AUC: 0.89, 95% CI 0.83–0.95, P < 0.0001). Levels of cfDNA were highest in patients with the most severe injury, i.e., ASIA A, compared with those with ASIA B (P = 0.04), ASIA C (P = 0.009), and ASIA D injuries (P < 0.001). Dimensionality reduction identified 4 candidate proteins (FABP3, REST, IL-6, NF-H) that were integrated with spinal cord–derived cfDNA to derive the Spinal Cord Injury Index (SCII), which has high sensitivity and specificity for SCI diagnosis (AUC: 0.91, 95% CI 0.82–0.99, P < 0.0001), correlates with injury severity (P < 0.0001), and predicts 6-month neurologic improvement (AUC: 0.77, 95% CI 0.61–0.93, P = 0.006).CONCLUSION The detection of spinal cord–derived cfDNA and plasma protein alterations as part of a multi-analyte blood test can inform SCI diagnosis and prognosis.FUNDING North American Spine Society Young Investigator Award; Morton Cure Paralysis Fund.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Tej D. Azad, Kathleen R. Ran, Joshua D. Materi, Divyaansh Raj, Timour Al-Khindi, Sameer Gabbita, Marvin Li, Elizabeth T. Wang, A. Karim Ahmed, Megan Parker, Anita L. Kalluri, Daniel Lubelski, Christopher M. Jackson, Daniel M. Sciubba, Jon D. Weingart, Ali Bydon, Timothy F. Witham, David W. Nauen, Srinivasan Yegnasubramanian, Nicholas Theodore, Chetan Bettegowda</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/176631">Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated <i>BRAF</i> mutant mouse models</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176631">Minkyung Kang, … , Chul Hoon Kim, Yong-Seok Lee</a> <a class='hide-for-small show-more' data-reveal-id='article45798-more' href='#'> <div class='article-authors'> Minkyung Kang, … , Chul Hoon Kim, Yong-Seok Lee </div> </a> <span class='article-published-at'> Published February 18, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI176631">https://doi.org/10.1172/JCI176631</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176631">Text</a> | <a href="/articles/view/176631/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI176631' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45798-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176631">Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated <i>BRAF</i> mutant mouse models</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176631">Text</a></li> <li><a class="button tiny" href="/articles/view/176631/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although BRAF gene mutations are associated with cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, it remains unclear how these mutations impair cognition. Here, we investigated the underlying neural mechanisms using several mouse models harboring a gain-of-function BRAF mutation (K499E) discovered in RASopathy patients. We found expressing BRAF K499E (KE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAFKE/+) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF KE expression in neural stem cells led to aberrant reactive astrogliosis, increased astrocytic Ca2+ fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific AAV-BRAF KE delivery induced memory deficits, reactive astrogliosis, and increased astrocytic Ca2+ fluctuations. Notably, reducing ERK activity in astrocytes rescued the memory deficits and altered astrocytic Ca2+ activity of Nestin;BRAFKE/+ mice. Furthermore, reducing astrocyte Ca2+ activity rescued the spatial memory impairments of BRAF KE-expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca2+ dysregulation, leading to the memory deficits of BRAF-associated RASopathies.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Minkyung Kang, Jihye Choi, Jeongho Han, Toshiyuki Araki, Soo-Whee Kim, Hyun-Hee Ryu, Min-Gyun Kim, Seoyeon Kim, Hanbyul Jang, Sun Yong Kim, Kyoung-Doo Hwang, Soobin Kim, Myeongjong Yoo, Jaegeon Lee, Kitae Kim, Pojeong Park, Ja Eun Choi, Dae Hee Han, Yujin Kim, Jeongyeon Kim, Sunghoe Chang, Bong-Kiun Kaang, Jung Min Ko, Keun-Ah Cheon, Joon-Yong An, Sang Jeong Kim, Hyungju Park, Benjamin G. Neel, Chul Hoon Kim, Yong-Seok Lee</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182931">Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182931">Geoffrey Canet, … , Esther M. Blessing, Emmanuel Planel</a> <a class='hide-for-small show-more' data-reveal-id='article45746-more' href='#'> <div class='article-authors'> Geoffrey Canet, … , Esther M. Blessing, Emmanuel Planel </div> </a> <span class='article-published-at'> Published February 4, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI182931">https://doi.org/10.1172/JCI182931</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182931">Text</a> | <a href="/articles/view/182931/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI182931' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45746-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182931">Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182931">Text</a></li> <li><a class="button tiny" href="/articles/view/182931/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Sleep disturbance is bidirectionally associated with increased risks of Alzheimer’s disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial given evidence indicates that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combine in vitro, in vivo and clinical methods to reveal a pathway by which changes in body temperature (BT) over the sleep-wake cycle modulate extracellular tau levels. In mice, higher BT during wakefulness and sleep-deprivation increased CSF and plasma tau levels, while also upregulating unconventional protein secretion pathway-I (UPS-I) components, including (i) intracellular tau dephosphorylation, (ii) caspase-3-mediated cleavage of tau (TauC3) and (iii) its membrane translocation through binding to PIP2 and syndecan-3. In humans, the increase in CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. By demonstrating that sleep-wake variation in BT regulates extracellular tau levels, our findings highlight the importance of thermoregulation in linking sleep disturbances to tau-mediated neurodegeneration, and the preventative potential of thermal interventions.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Geoffrey Canet, Felipe Da Gama Monteiro, Emma Rocaboy, Sofia Diego-Diaz, Boutheyna Khelaifia, Kelly Godbout, Aymane Lachhab, Jessica Kim, Daphne I. Valencia, Audrey Yin, Hau-Tieng Wu, Jordan C. Howell, Emily Blank, Francis Laliberté, Nadia Fortin, Emmanuelle Boscher, Parissa Fereydouni-Forouzandeh, Stéphanie Champagne, Isabelle Guisle, Sébastien S. Hébert, Vincent Pernet, Haiyan Liu, William Lu, Ludovic Debure, David M. Rapoport, Indu Ayappa, Andrew W. Varga, Ankit Parekh, Ricardo S. Osorio, Steve Lacroix, Mark P. Burns, Brendan P. Lucey, Esther M. Blessing, Emmanuel Planel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182584">Neonatal but not Juvenile Gene Therapy Reduces Seizures and Prolongs Lifespan in SCN1B-Dravet Syndrome Mice</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182584">Chunling Chen, … , David R. Hampson, Lori L. Isom</a> <a class='hide-for-small show-more' data-reveal-id='article45714-more' href='#'> <div class='article-authors'> Chunling Chen, … , David R. Hampson, Lori L. Isom </div> </a> <span class='article-published-at'> Published January 23, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI182584">https://doi.org/10.1172/JCI182584</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182584">Text</a> | <a href="/articles/view/182584/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI182584' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45714-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182584">Neonatal but not Juvenile Gene Therapy Reduces Seizures and Prolongs Lifespan in SCN1B-Dravet Syndrome Mice</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182584">Text</a></li> <li><a class="button tiny" href="/articles/view/182584/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) that begins in the first year of life. While most cases of DS are caused by variants in SCN1A, variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are also linked to DS or to the more severe early infantile DEE. Both disorders fall under the OMIM term DEE52. Scn1b null mice model DEE52, with spontaneous generalized seizures and death in 100% of animals in the third postnatal week. Scn1b null cortical parvalbumin-positive interneurons and pyramidal neurons are hypoexcitable. The goal of this study was to develop a proof-of-principle gene replacement strategy for DEE52. We tested an adeno-associated viral vector encoding β1 subunit cDNA (AAV-Navβ1) in Scn1b null mice. We demonstrated that AAV-Navβ1 drives β1 protein expression in excitatory and inhibitory neurons in mouse brain. Bilateral intracerebroventricular administration of AAV-Navβ1 in Scn1b null mice at postnatal day (P) 2, but not at P10, reduced spontaneous seizure severity and duration, prolonged life span, prevented hyperthermia-induced seizures, and restored cortical neuron excitability. AAV-Navβ1 administration to WT mice resulted in β1 overexpression in brain but no obvious adverse effects. This work lays the foundation for future development of a gene therapeutic strategy for SCN1B-linked DEE patients. </p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Chunling Chen, Yukun Yuan, Heather A. O'Malley, Robert Duba-Kiss, Yan Chen, Karl Habig, Yosuke Niibori, Samantha L. Hodges, David R. Hampson, Lori L. Isom</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/171077">PDGFRα inhibition reduces myofibroblast expansion in the fibrotic rim and enhances recovery after ischemic stroke</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/171077">Jil Protzmann, … , Daniel A. Lawrence, Linda Fredriksson</a> <a class='hide-for-small show-more' data-reveal-id='article45676-more' href='#'> <div class='article-authors'> Jil Protzmann, … , Daniel A. Lawrence, Linda Fredriksson </div> </a> <span class='article-published-at'> Published January 14, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI171077">https://doi.org/10.1172/JCI171077</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/171077">Text</a> | <a href="/articles/view/171077/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI171077' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45676-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/171077">PDGFRα inhibition reduces myofibroblast expansion in the fibrotic rim and enhances recovery after ischemic stroke</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/171077">Text</a></li> <li><a class="button tiny" href="/articles/view/171077/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Ischemic stroke is a major cause of adult disability. Early treatment with thrombolytics and/or thrombectomy can significantly improve outcomes; however, following these acute interventions, treatment is limited to rehabilitation therapies. Thus, the identification of therapeutic strategies that can help restore brain function in the post-acute phase remains a major challenge. Here we report that genetic or pharmacologic inhibition of the PDGF-CC/PDGFRα pathway, which has previously been implicated in stroke pathology, significantly reduced myofibroblast expansion in the border of the fibrotic scar and improved outcome in a sensory-motor integration test after experimental ischemic stroke. This was supported by gene expression analyses of cerebrovascular fragments, showing upregulation of pro-fibrotic/pro-inflammatory genes, including genes of the TGFβ pathway, after ischemic stroke or intracerebroventricular injection of active PDGF-CC. Further, longitudinal intravital two-photon imaging revealed that inhibition of PDGFRα dampened the bi-phasic pattern of stroke-induced vascular leakage and enhanced vascular perfusion in the ischemic lesion. Importantly, we found efficacy of PDGFRα inhibition on functional recovery when initiated 24 hours after ischemic stroke. Our data implicate the PDGF-CC/PDGFRα pathway as a crucial mediator modulating post-stroke pathology and suggest a post-acute treatment opportunity for ischemic stroke patients targeting myofibroblast expansion to foster long-term CNS repair.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jil Protzmann, Manuel Zeitelhofer, Christina Stefanitsch, Daniel Torrente, Milena Z. Adzemovic, Kirils Matjunins, Stella J.I. Randel, Sebastian A. Lewandowski, Lars Muhl, Ulf Eriksson, Ingrid Nilsson, Enming J. Su, Daniel A. Lawrence, Linda Fredriksson</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/32?content=articles&page=2">2</a></li> <li><a href="/tags/32?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/32?content=articles&page=62">62</a></li> <li><a href="/tags/32?content=articles&page=63">63</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/32?content=articles&page=2">Next →</a></li></ul></div> </div> </div> </div> <div class='content ' id='posts'> <div class='row'> <div class='small-12 columns'> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/360">DREAM suppression in Huntington’s disease</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/360"><div class='article-metadata'> José Naranjo and colleagues reveal that downregulation of DREAM mediates derepression of ATF6, and this elevation of ATF6 plays an early neuroprotective role in Huntington’s disease… <br> <span class='published-at smaller'> Published January 11, 2016 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/32"><span style='margin-right: 6px' class="label-specialty">Neuroscience</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/360"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/417/thumb_Fig_6C_unlabeled.jpg" /></a> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/341">Extra-cerebellar motor symptoms in Angelman’s syndrome </a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/341"><div class='article-metadata'> Caroline Bruinsma and colleagues evaluated cerebellar involvement in Angelman’s Syndrome motor deficits… <br> <span class='published-at smaller'> Published October 20, 2015 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/32"><span style='margin-right: 6px' class="label-specialty">Neuroscience</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/341"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/403/thumb_Showstopper.jpg" /></a> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/324">An epigenetic intervention for neurodegenerative diseases</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/324"><div class='article-metadata'> Eva Benito and colleagues demonstrate that SAHA, a histone-deacetylase inhibitor, improves spatial memory and selectively regulates the neuronal epigenome in a mouse model of neurodegeneration… <br> <span class='published-at smaller'> Published August 17, 2015 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/32"><span style='margin-right: 6px' class="label-specialty">Neuroscience</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/324"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/390/thumb_Benito_small.jpg" /></a> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/302">Genetic and environmental interactions in Parkinson’s disease</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/302"><div class='article-metadata'> Alevtina Zharikov and colleagues reveal that interplay between α-synuclein and environmental toxin exposure influences parkinsonian neurodegeneration… <br> <span class='published-at smaller'> Published June 15, 2015 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/32"><span style='margin-right: 6px' class="label-specialty">Neuroscience</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/302"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/375/thumb_64502_Zharikov_et_al_July_C.jpg" /></a> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/281">TREM2 keeps myelinated axons under wraps</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/281"><div class='article-metadata'> Pietro Poliani, Yaming Wang, and colleagues demonstrate that TREM2 deficiency reduces age-associated expansion of microglia and microglia-dependent remyelination… <br> <span class='published-at smaller'> Published April 20, 2015 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/32"><span style='margin-right: 6px' class="label-specialty">Neuroscience</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/281"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/360/thumb_77983.jpg" /></a> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/276">Synergy among Parkinson’s disease-associated genes</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/276"><div class='article-metadata'> Durga Meka and colleagues demonstrate that crosstalk between parkin and RET maintains mitochondrial integrity and protects dopaminergic neurons… <br> <span class='published-at smaller'> Published March 30, 2015 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/32"><span style='margin-right: 6px' class="label-specialty">Neuroscience</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/276"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/355/thumb_79300.jpg" /></a> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/264">A model of periventricular leukomalacia</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/264"><div class='article-metadata'> Tamar Licht, Talia Dor-Wollman and colleagues demonstrate that specific vulnerability of immature blood vessels surrounding ventricles predisposes to hypoxia-induced periventricular leukomalacia… <br> <span class='published-at smaller'> Published February 17, 2015 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/32"><span style='margin-right: 6px' class="label-specialty">Neuroscience</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/264"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/348/thumb_HP11_30015.jpg" /></a> </div> </div> </div> </div> <div class='row'> <div class='small-12 columns'> </div> </div> </div> </div> </div> <div class='large-2 medium-3 hide-for-small columns' style='padding: 12px 9px 12px 9px;'> <div style='width:100%; text-align: center;'> <div id='jci-interior-skyscraper-right-col'> <span class='secondary label'>Advertisement</span> <script> try { googletag.cmd.push(function () { googletag.display('jci-interior-skyscraper-right-col'); }); } catch(e){} </script> </div> </div> </div> </div> </div> </div> </div> </div> <div id='footer'> <div class='row panel-padding'> <div class='small-6 columns'> <div id='social-links'> <a onclick="trackOutboundLink('/twitter?ref=footer');" href="/twitter"><img title="Twitter" src="/assets/social/twitter-round-blue-78025a92064e3594e44e4ccf5446aefeafba696cd3c8e4a7be1850c7c9f62aba.png" /></a> <a onclick="trackOutboundLink('/facebook?ref=footer');" href="/facebook"><img title="Facebook" src="/assets/social/facebook-round-blue-2787910d46dcbdbee4bd34030fee044e5a77cfda2221af9191d437b2f5fadeb1.png" /></a> <a href="/rss"><img title="RSS" src="/assets/social/rss-round-color-6f5fa8e93dc066ee4923a36ba6a7cb97d53c5b77de78a2c7b2a721adc603f342.png" /></a> </div> <br> Copyright © 2025 <a href="http://www.the-asci.org">American Society for Clinical Investigation</a> <br> ISSN: 0021-9738 (print), 1558-8238 (online) </div> <div class='small-6 columns'> <div class='row'> <div class='small-12 columns'> <h4 class='notices-signup'>Sign up for email alerts</h4> <form action='https://notices.jci.org/subscribers/new' method='get'> <input name='utm_source' type='hidden' value='jci'> <input name='utm_medium' type='hidden' value='web'> <input name='utm_campaign' type='hidden' value='email_signup'> <input name='utm_content' type='hidden' value='footer'> <div class='row'> <div class='small-12 medium-9 columns'> <input name='email_address' placeholder='Your email address' required type='text'> </div> <div class='small-12 medium-3 columns'> <input class='button tiny orange' type='submit' value='Sign up'> </div> </div> </form> </div> </div> </div> </div> </div> </div> <script src="/assets/application-27f18b5fe3b7302e5b3e3c6d7cf9bb3f54759fad32679209f5aef429b89f3aef.js"></script>  <script src="//s7.addthis.com/js/300/addthis_widget.js#pubid=ra-4d8389db4b0bb592" async="async"></script> <script src="//d1bxh8uas1mnw7.cloudfront.net/assets/embed.js" async="async"></script>  </body> </html>