{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:06:31Z","timestamp":1789153591151,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1014701","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000}}],"reference-count":73,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"NIMH","doi-asserted-by":"crossref","award":["R01MH86638"],"award-info":[{"award-number":["R01MH86638"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Ischemia, whether abrupt or chronic, limits ATP production and disrupts ATP-dependent homeostatic mechanisms, leading to alterations in both intracellular and extracellular ion concentrations. Inadequate neuronal ATP triggers K\n                    <jats:sup>+<\/jats:sup>\n                    release and increased extracellular K\n                    <jats:sup>+<\/jats:sup>\n                    depolarizes neurons, leading to additional K\n                    <jats:sup>+<\/jats:sup>\n                    release; this positive feedback phenomenon is known as spreading depolarization (SD). When the depolarizing effects are strong enough, the cells undergo depolarization blockade, known as spreading depression. Excess extracellular K\n                    <jats:sup>+<\/jats:sup>\n                    increases energy demand from the Na\n                    <jats:sup>+<\/jats:sup>\n                    -K\n                    <jats:sup>+<\/jats:sup>\n                    pump, producing a pathological confluence of increased demand with reduced delivery of energy. The resulting changes have profound effects at subcellular, cellular, and network scales of brain function. We hypothesized that consequences of ischemic or SD homeostatic failure would differ on the subcellular scale, with differences between disjunct dendritic regions of a hippocampal CA1 pyramidal neuron. To evaluate the interplay between morphology and ion concentrations, we used a mechanistic simulation incorporating neuronal morphology, pumps, exchangers, voltage-, and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -sensitive ion channels. In both cases, calcium accumulation was greatest in the basal dendrites, suggesting these dendrites would show the greatest effects of excitotoxicity. By contrast, in ischemia, but not in SD, distal apical dendrites were exposed to greater intracellular chloride concentrations, which may lead to dendritic beading.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014701","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:44:05Z","timestamp":1788889445000},"page":"e1014701","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computer models predict differential dendritic vulnerability with ischemia and spreading depression"],"prefix":"10.1371","volume":"22","author":[{"given":"Adam J. H.","family":"Newton","sequence":"first","affiliation":[{"name":"Yale School of Public Health","place":["New Haven, Connecticut, United States of America"],"department":["Department of Biostatistics"]},{"name":"SUNY Downstate Health Sciences University","place":["Brooklyn, New York, United States of America"],"department":["Department of Physiology and Pharmacology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William W.","family":"Lytton","sequence":"additional","affiliation":[{"name":"SUNY Downstate Health Sciences University","place":["Brooklyn, New York, United States of America"],"department":["Department of Physiology and Pharmacology"]},{"name":"Kings County Hospital Center","place":["Brooklyn, New York, United States of America"],"department":["Department of Neurology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"DiStasio","sequence":"additional","affiliation":[{"name":"Yale School of Medicine","place":["New Haven, Connecticut, United States of America"],"department":["Department of Pathology"]},{"name":"Yale School of Medicine","place":["New Haven, Connecticut, United States of America"],"department":["Department of Ophthalmology and Visual Science"]},{"name":"Wu Tsai Institute, Yale University","place":["New Haven, Connecticut, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6394-3127","authenticated-orcid":true,"given":"Robert A.","family":"McDougal","sequence":"additional","affiliation":[{"name":"Yale School of Public Health","place":["New Haven, Connecticut, United States of America"],"department":["Department of Biostatistics"]},{"name":"Wu Tsai Institute, Yale University","place":["New Haven, Connecticut, United States of America"]},{"name":"Yale School of Medicine","place":["New Haven, Connecticut, United States of America"],"department":["Department of Biomedical Informatics and Data Science"]},{"name":"Program in 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Attwell","year":"2001","journal-title":"J Cereb Blood Flow Metab"},{"issue":"4","key":"pcbi.1014701.ref003","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nm.2333","article-title":"The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease","volume":"17","author":"JP Dreier","year":"2011","journal-title":"Nat Med"},{"issue":"29","key":"pcbi.1014701.ref004","doi-asserted-by":"crossref","first-page":"9859","DOI":"10.1523\/JNEUROSCI.1917-10.2010","article-title":"Recurrent spontaneous spreading depolarizations facilitate acute dendritic injury in the ischemic penumbra","volume":"30","author":"WC Risher","year":"2010","journal-title":"J Neurosci"},{"key":"pcbi.1014701.ref005","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780195151718.001.0001","volume-title":"Ions in the brain: normal function, seizures, and stroke","author":"GG 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Hasbani","year":"1998","journal-title":"Exp Neurol"},{"issue":"9","key":"pcbi.1014701.ref018","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1006423","article-title":"The physiological variability of channel density in hippocampal CA1 pyramidal cells and interneurons explored using a unified data-driven modeling workflow","volume":"14","author":"R Migliore","year":"2018","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1014701.ref019","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2202-15-S1-P108","article-title":"Calcium regulation of HCN supports persistent activity associated with working memory: a multiscale model of prefrontal cortex","volume":"15","author":"SA Neymotin","year":"2014","journal-title":"BMC Neurosci"},{"issue":"10","key":"pcbi.1014701.ref020","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1005804","article-title":"The role of glutamate in neuronal ion homeostasis: A case study of spreading depolarization","volume":"13","author":"N 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Swann","year":"2000","journal-title":"Hippocampus"},{"issue":"2","key":"pcbi.1014701.ref030","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1006\/exnr.1994.1170","article-title":"Functional and morphological changes induced by transient in vivo ischemia","volume":"129","author":"N Hori","year":"1994","journal-title":"Exp Neurol"},{"issue":"7","key":"pcbi.1014701.ref031","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1523\/JNEUROSCI.5128-07.2008","article-title":"Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines","volume":"28","author":"TH Murphy","year":"2008","journal-title":"J Neurosci"},{"issue":"53","key":"pcbi.1014701.ref032","doi-asserted-by":"crossref","first-page":"8619","DOI":"10.1038\/sj.onc.1207105","article-title":"Calcium and apoptosis: facts and hypotheses","volume":"22","author":"R Rizzuto","year":"2003","journal-title":"Oncogene"},{"issue":"2","key":"pcbi.1014701.ref033","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s10827-006-0001-y","article-title":"Seizure-like afterdischarges simulated in a model neuron","volume":"22","author":"H Kager","year":"2007","journal-title":"J Comput Neurosci"},{"issue":"4","key":"pcbi.1014701.ref034","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.neuroscience.2004.06.074","article-title":"Na(+) and Ca(2+) homeostasis pathways, cell death and protection after oxygen-glucose-deprivation in organotypic hippocampal slice cultures","volume":"128","author":"M Mart\u00ednez-S\u00e1nchez","year":"2004","journal-title":"Neuroscience"},{"issue":"1","key":"pcbi.1014701.ref035","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1161\/01.STR.30.1.171","article-title":"Sodium influx plays a major role in the membrane depolarization induced by oxygen and glucose deprivation in rat striatal spiny neurons","volume":"30","author":"P Calabresi","year":"1999","journal-title":"Stroke"},{"issue":"7","key":"pcbi.1014701.ref036","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1083\/jcb.201803152","article-title":"Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism","volume":"217","author":"G Yellen","year":"2018","journal-title":"J Cell Biol"},{"issue":"42","key":"pcbi.1014701.ref037","doi-asserted-by":"crossref","first-page":"13983","DOI":"10.1523\/JNEUROSCI.2040-10.2010","article-title":"The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy","volume":"30","author":"F Boumezbeur","year":"2010","journal-title":"J Neurosci"},{"issue":"24","key":"pcbi.1014701.ref038","doi-asserted-by":"crossref","first-page":"13273","DOI":"10.1073\/pnas.94.24.13273","article-title":"The synthesis of ATP by glycolytic enzymes in the postsynaptic density and the effect of endogenously generated nitric oxide","volume":"94","author":"K Wu","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"pcbi.1014701.ref039","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S0306-4522(00)00496-6","article-title":"Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells","volume":"102","author":"M Meg\u00edas","year":"2001","journal-title":"Neuroscience"},{"issue":"1","key":"pcbi.1014701.ref040","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1002\/cne.903600111","article-title":"Dendritic morphology of CA1 pyramidal neurones from the rat hippocampus: I. Branching patterns","volume":"360","author":"NJ Bannister","year":"1995","journal-title":"J Comp Neurol"},{"key":"pcbi.1014701.ref041","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.neuroscience.2011.12.055","article-title":"Non-homogeneous stereological properties of the rat hippocampus histological sections","volume":"205","author":"D Ropireddy","year":"2012","journal-title":"Neuroscience"},{"issue":"5","key":"pcbi.1014701.ref042","doi-asserted-by":"crossref","first-page":"112478","DOI":"10.1016\/j.celrep.2023.112478","article-title":"Nanoscale and functional heterogeneity of the hippocampal extracellular space","volume":"42","author":"D Grassi","year":"2023","journal-title":"Cell Rep"},{"issue":"1","key":"pcbi.1014701.ref043","doi-asserted-by":"crossref","first-page":"3190","DOI":"10.1038\/s41467-021-23508-y","article-title":"Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular 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Neurosci"},{"issue":"32","key":"pcbi.1014701.ref047","doi-asserted-by":"crossref","first-page":"8014","DOI":"10.1523\/JNEUROSCI.0765-08.2008","article-title":"Zn2+ influx is critical for some forms of spreading depression in brain slices","volume":"28","author":"RM Dietz","year":"2008","journal-title":"J Neurosci"},{"issue":"4","key":"pcbi.1014701.ref048","doi-asserted-by":"crossref","DOI":"10.1523\/ENEURO.0082-22.2022","article-title":"Multiscale Computer Modeling of Spreading Depolarization in Brain Slices","volume":"9","author":"C Kelley","year":"2022","journal-title":"eNeuro"},{"issue":"5","key":"pcbi.1014701.ref049","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1085\/jgp.95.5.837","article-title":"Intracellular and extracellular changes of [Ca2+] in hypoxia and ischemia in rat brain in vivo","volume":"95","author":"IA Silver","year":"1990","journal-title":"J Gen Physiol"},{"issue":"3","key":"pcbi.1014701.ref050","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1161\/01.STR.29.3.705","article-title":"Calcium in ischemic cell death","volume":"29","author":"T Kristi\u00e1n","year":"1998","journal-title":"Stroke; a journal of cerebral circulation"},{"issue":"1","key":"pcbi.1014701.ref051","doi-asserted-by":"crossref","first-page":"4444","DOI":"10.1038\/s41467-022-32130-5","article-title":"A\u03b242 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy","volume":"13","author":"A Lee","year":"2022","journal-title":"Nat Commun"},{"issue":"2","key":"pcbi.1014701.ref052","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1152\/jn.1995.74.2.565","article-title":"Extracellular potassium, volume fraction, and tortuosity in rat hippocampal CA1, CA3, and cortical slices during ischemia","volume":"74","author":"MA P\u00e9rez-Pinz\u00f3n","year":"1995","journal-title":"J Neurophysiol"},{"issue":"5","key":"pcbi.1014701.ref053","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1007\/s11064-005-2753-6","article-title":"Endoplasmic reticulum dysfunction and Ca2+ deregulation in isolated CA1 neurons during oxygen and glucose deprivation","volume":"30","author":"GA Larsen","year":"2005","journal-title":"Neurochem Res"},{"issue":"11","key":"pcbi.1014701.ref054","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1038\/jcbfm.2015.137","article-title":"Selective neuronal vulnerability of human hippocampal CA1 neurons: lesion evolution, temporal course, and pattern of hippocampal damage in diffusion-weighted MR imaging","volume":"35","author":"T Bartsch","year":"2015","journal-title":"J Cereb Blood Flow Metab"},{"key":"pcbi.1014701.ref055","first-page":"1","article-title":"NEURON Simulation Environment.","volume-title":"Encyclopedia of Computational Neuroscience","author":"M Hines","year":"2019"},{"key":"pcbi.1014701.ref056","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511541612","volume-title":"The NEURON book","author":"NT Carnevale","year":"2006"},{"key":"pcbi.1014701.ref057","doi-asserted-by":"crossref","DOI":"10.3389\/fninf.2013.00028","article-title":"Reaction-diffusion in the NEURON simulator","volume":"7","author":"RA McDougal","year":"2013","journal-title":"Frontiers in Neuroinformatics"},{"key":"pcbi.1014701.ref058","doi-asserted-by":"crossref","first-page":"41","DOI":"10.3389\/fninf.2018.00041","article-title":"Using NEURON for Reaction-Diffusion Modeling of Extracellular Dynamics","volume":"12","author":"AJH Newton","year":"2018","journal-title":"Front Neuroinform"},{"issue":"14","key":"pcbi.1014701.ref059","doi-asserted-by":"crossref","first-page":"6538","DOI":"10.1016\/S0021-9258(18)50401-4","article-title":"Cytosolic phosphorylation potential","volume":"254","author":"RL Veech","year":"1979","journal-title":"J Biol 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