Glial Swelling in Ischemia: A Hypothesis

Abstract

On the basis of experiments with primary cultures of mouse astrocytes with conventional K⁺-sensitive intracellular microelectrodes involving ''chemical ischemia'' (antimycin a and sodium fluoride treatment), a model of ischemia is presented. According to this model, ischemia has no significant direct effect during the first 10 min on astrocytes; neurones, however, lose a major part of their K⁺ into the ECS. This leads to an astrocytic depolarization, which in turn activates astrocytic anion channels. This will result in passive, Donnan-mediated K⁺, CI^– and HCO3̄ fluxes into astrocytes, which in turn causes swelling and a collapse of the ECS. Arguments are put forward that this may explain the swelling of astrocytic endfeet, which occurs very early in an ischemic insult.

Ischemia-Induced Changes in the Extracellular Space Diffusion Parameters, K+, and pH in the Developing Rat Cortex and Corpus Callosum

“…Table 2 summarizes ECS ionic composition, volume, and geometry during phases I-IV of our experiments and suggests the ratio of neuron/glia swelling. It is, in addition to the findings in our present study, based on previous findings about neuronal and glial swelling during ischemia (for a review, see Han sen and Zeuthen, 1981;Sykova, 1983;Walz et aI., 1993;Siesjo, 1993;Szatkovski and Attwell, 1994;Siesjo et aI., 1995). During phase I, in which we see no statistically significant change in ECS volume and geometry, we can assume that energy depletion is low, since the anaerobic metabolism is maintaining active N a + /K + transport.…”

“…During phase I, in which we see no statistically significant change in ECS volume and geometry, we can assume that energy depletion is low, since the anaerobic metabolism is maintaining active N a + /K + transport. The transient increase in spike activity is accompanied by a calcium-dependent K+ rise in the ECS of 1-2 mM (Walz et aI., 1993), a small acid shift in pHc (see Fig. 3), normal levels of [Na+]e and [Ca+2]c (Xie et aI., 1995), and a positive shift in DC signals.…”

“…It is, therefore, reasonable to as sume that neurons especially, and not glial cells, are swelling (see Walz et aI., 1993). At phase III, the severe energy depletion results in complete loss of ionic homeostasis: [K+]e is elevated by 50-70 mM, [Na+]c and [Ca+2]e rapidly decrease (Xie et aI., 1995), and pHe decreases by �0.5-0.6 pH units.…”

“…5). During this phase, glial cells are depolarized; the depolarization leads to an opening of anion (CI-and HC0 3 -) channels, and this, in turn, results in passive, Donnan-mediated K+, CI-, and HC03 -fluxes into glial cells, particularly astrocytes (for review, see Walz et aI., 1993). This naturally leads to water accumulation in astrocytes at the expense of ECS, ECS volume decreases, and tortuosity increases, all with approximately the same time course (see Figs.…”

“…Neuronal and glial cell swelling during an energy deficit is the consequence of transmembrane ionic shifts resulting in the intracellular accumulation of K+, Ca2+, or Na+ and accompanied by an influx of water due to osmotic imbalance (for reviews see Sy kova, 1983;Kimelberg and Ransom, 1986;Sykova, 1992;Walz et aI., 1993). Anoxia/ischemia and, to a lesser degree, hypoxia or partial ischemia result in a dramatic decrease in extracellular space (ECS) vol ume and a decrease in the apparent diffusion coeffi cient (ADC) of tetramethylammonium (TMA +) or tetraethylammonium (TEA +) Lundbaek and Hansen, 1992;Sykova et aI., 1994b;Perez-Pinzon et aI., 1995) or ADC of water (Van der Toorn et aI., 1996), apparently due to cellu lar swelling.…”