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Computer models predict differential dendritic vulnerability with ischemia and spreading depression.

Overview

Authors: Adam J H Newton1,2, William W Lytton2,3, Marcello DiStasio4,5,6, Robert A McDougal1,6,7,8,9
ORCID iDs: Adam J H Newton, William W Lytton, Marcello DiStasio, Robert A McDougal
  1. Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, United States of America
  2. Department of Physiology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, New York, United States of America
  3. Department of Neurology, Kings County Hospital Center, Brooklyn, New York, United States of America
  4. Department of Pathology, Yale School of Medicine, New Haven, Connecticut, United States of America
  5. Department of Ophthalmology and Visual Science, Yale School of Medicine, New Haven, Connecticut, United States of America
  6. Wu Tsai Institute, Yale University, New Haven, Connecticut, United States of America
  7. Department of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, Connecticut, United States of America
  8. Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America
  9. Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut, United States of America
Institutions: SUNY Downstate Health Sciences University (United States); Yale University (United States); Kings County Hospital Center (United States)
Journal: PLoS computational biology, volume 22, issue 9, article e1014701
Dates: received 18 January 2026; accepted 10 August 2026; published online 8 September 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1371/journal.pcbi.1014701 · PMID 42709853 · PMCID PMC13568529 · OpenAlex W4414523368
Open access: gold, a free copy (OpenAlex)
Preprint: doi:10.1101/2025.09.22.677786
Status: code verified (how the code is found and verified)
Categories: computational modeling (no new data) (modality), human (organism), computational (subfield)
Methods: fMRI & imaging
MeSH: Brain Ischemia*, Cortical Spreading Depression*, Dendrites*, Models, Neurological*, Animals, CA1 Region, Hippocampal, Calcium, Computational Biology, Computer Simulation, Humans, Potassium, Pyramidal Cells (* major topic)
Topic: Neuroscience and Neuropharmacology Research (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: NIMH (R01MH86638); NIMH NIH HHS (R01 MH086638)
Citations: not cited yet (Europe PMC); 73 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

modeldb:244688

License: none: the authors keep all their rights
State: the link answers, verified on 26 September 2026
Evidence: the link answers
Software Heritage: not checked
Found in: the text, “4. Materials and methods”
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 26 September 2026: the link answers (HTTP 200)
  • 26 September 2026: the link answers (HTTP 200)
At the source: modeldb.science/244688

modeldb:185858

License: none: the authors keep all their rights
State: the link answers, verified on 26 September 2026
Evidence: the link answers
Software Heritage: not checked
Found in: the text, “4.4. Calcium dynamics”
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 26 September 2026: the link answers (HTTP 200)
  • 26 September 2026: the link answers (HTTP 200)
At the source: modeldb.science/185858

modeldb:2017004

License: none: the authors keep all their rights
State: the link answers, verified on 26 September 2026
Evidence: the link answers
Software Heritage: not checked
Found in: “Data Availability”
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 26 September 2026: the link answers (HTTP 200)
  • 26 September 2026: the link answers (HTTP 200)
At the source: modeldb.science/2017004

The paper's code and data availability statement is in the Data section.

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Data

No dataset and no data link were found in the paper.

Data Availability

All model code is available at https://modeldb.science/2017004.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 3, 28 September 2026

  • Authors: added Adam J H Newton (0000-0002-4726-2644); William W Lytton (0000-0002-3727-2849); Marcello DiStasio (0000-0001-6588-0713); removed Adam J H Newton; William W Lytton; Marcello DiStasio

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 12 MeSH terms, 2 funders, 71 references.

Cite

This paper

Newton, A. J. H., Lytton, W. W., DiStasio, M., & McDougal, R. A. (2026). Computer models predict differential dendritic vulnerability with ischemia and spreading depression. PLoS computational biology, 22(9), e1014701. https://doi.org/10.1371/journal.pcbi.1014701

BibTeX

@article{newton2026computer,
author = {Newton, Adam J H and Lytton, William W and DiStasio, Marcello and McDougal, Robert A},
title = {{Computer models predict differential dendritic vulnerability with ischemia and spreading depression}},
journal = {PLoS computational biology},
year = {2026},
month = sep,
volume = {22},
number = {9},
pages = {e1014701},
publisher = {PLOS},
issn = {1553-734X},
doi = {10.1371/journal.pcbi.1014701},
url = {https://doi.org/10.1371/journal.pcbi.1014701},
pmid = {42709853},
pmcid = {PMC13568529}
}

RIS

TY - JOUR
AU - Newton, Adam J H
AU - Lytton, William W
AU - DiStasio, Marcello
AU - McDougal, Robert A
TI - Computer models predict differential dendritic vulnerability with ischemia and spreading depression
T2 - PLoS computational biology
J2 - PLoS Comput Biol
PY - 2026
DA - 2026/09/08
VL - 22
IS - 9
SP - e1014701
SN - 1553-734X
PB - PLOS
DO - 10.1371/journal.pcbi.1014701
UR - https://doi.org/10.1371/journal.pcbi.1014701
LA - en
ER -

CSL-JSON

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