{
  "abstract": "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+ release and increased extracellular K+ depolarizes neurons, leading to additional K+ 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+ increases energy demand from the Na+-K+ 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 Ca2+-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. Author summary: Neurons are cells, and like all cells, they respond to changes in their environment. Different conditions, such as ischemia and elevated potassium concentrations, can trigger a response known as spreading depression, where the membrane potential of the neuron is depolarized and the cell is unable to generate action potentials. To better understand the cellular response to these two conditions, we constructed a detailed simulation study incorporating a neuron, an astrocyte, and the nearby extracellular space. The astrocyte used a simplified morphology, while the neuron was considered in full morphological detail to examine how its different regions responded. Both cell models included ion channels, homeostatic mechanisms, and dynamic chemical concentrations. In both conditions, our model found that calcium concentration was most elevated in the basal dendrites. Ischemia led to elevated intracellular chloride concentrations in distal apical dendrites, while elevated potassium concentrations did not. Elevated calcium is associated with excitotoxicity, and elevated chloride has been associated with dendritic beading.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, United States of America",
    "Department of Physiology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, New York, United States of America",
    "Department of Neurology, Kings County Hospital Center, Brooklyn, New York, United States of America",
    "Department of Pathology, Yale School of Medicine, New Haven, Connecticut, United States of America"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
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        0
      ],
      "name": "Adam J. H. Newton"
    },
    {
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        1
      ],
      "name": "William W. Lytton"
    },
    {
      "affs": [
        2
      ],
      "name": "Marcello DiStasio"
    },
    {
      "affs": [
        3
      ],
      "name": "Robert A. McDougal"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8pwmmqr4r78zg.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pcbi.1014701",
  "fulltext_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014701",
  "id": "8pwmmqr4r78zg",
  "issns": [
    "1553-7358"
  ],
  "landing_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014701",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2738|Migraine and Headache Studies"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Neurochemistry/Neurotransmitters/Glutamate"
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    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Neurons"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Neurons/Neuronal dendrites"
    ],
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      "plos",
      "/Biology and life sciences/Cell biology/Hypoxia"
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      "plos",
      "/Biology and life sciences/Neuroscience/Cellular neuroscience/Neurons"
    ],
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      "plos",
      "/Biology and life sciences/Neuroscience/Cellular neuroscience/Neurons/Neuronal dendrites"
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      "/Biology and life sciences/Neuroscience/Neurochemistry/Neurotransmitters/Glutamate"
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      "/Biology and life sciences/Physiology/Electrophysiology/Membrane potential"
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    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Membrane potential/Depolarization"
    ],
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      "plos",
      "/Medicine and health sciences/Pulmonology/Medical hypoxia"
    ],
    [
      "plos",
      "/Medicine and health sciences/Vascular medicine/Ischemia"
    ]
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  "pdf_url": "https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1014701&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-08",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/8pwmmqr4r78zg.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:56Z",
      "native_id": "10.1371/journal.pcbi.1014701",
      "source": "plos",
      "url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014701"
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  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "plos:neuroscience",
      "subfield": "neuroscience"
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    {
      "field": "medicine",
      "origin": "plos:physiology",
      "subfield": "physiology"
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  "title": "Computer models predict differential dendritic vulnerability with ischemia and spreading depression",
  "title_text": "Computer models predict differential dendritic vulnerability with ischemia and spreading depression",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:56Z",
  "url": "https://research.draconitic.com/paper/8pwmmqr4r78zg",
  "venue": "PLOS Computational Biology",
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}