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

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.