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

Overview

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

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.

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Data Availability

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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

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