Abstract
Simultaneous changes in ion concentrations, glutamate, and cell volume together with exchange of matter between cell network and vasculature are ubiquitous in numerous brain pathologies. A complete understanding of pathological conditions as well as normal brain function, therefore, hinges on elucidating the molecular and cellular pathways involved in these mostly interdependent variations. In this paper, we develop the first computational framework that combines the Hodgkin–Huxley type spiking dynamics, dynamic ion concentrations and glutamate homeostasis, neuronal and astroglial volume changes, and ion exchange with vasculature into a comprehensive model to elucidate the role of glutamate uptake in the dynamics of spreading depolarization (SD)—the electrophysiological event underlying numerous pathologies including migraine, ischemic stroke, aneurysmal subarachnoid hemorrhage, intracerebral hematoma, and trauma. We are particularly interested in investigating the role of glutamate in the duration and termination of SD caused by K+ perfusion and oxygen-glucose deprivation. Our results demonstrate that glutamate signaling plays a key role in the dynamics of SD, and that impaired glutamate uptake leads to recovery failure of neurons from SD. We confirm predictions from our model experimentally by showing that inhibiting astrocytic glutamate uptake using TFB-TBOA nearly quadruples the duration of SD in layers 2-3 of visual cortical slices from juvenile rats. The model equations are either derived purely from first physical principles of electroneutrality, osmosis, and conservation of particles or a combination of these principles and known physiological facts. Accordingly, we claim that our approach can be used as a future guide to investigate the role of glutamate, ion concentrations, and dynamics cell volume in other brain pathologies and normal brain function.
Highlights
Spreading depolarization (SD) is a self-propagating wave characterized by a near-complete breakdown of transmembrane ion gradients in cells, sustained depolarization in individual neurons, and swelling of neuronal and glia cells [1, 2, 3, 4, 5]
Pathological conditions such as seizure, migraine, traumatic brain injury, and stroke are associated with extreme changes in ion concentrations and glutamate, cell swelling, and heavy exchange of matter between neurons, glia, and vasculature
Glutamate homeostasis and spreading depolarization experimental tools are capable of measuring only a few of these variables, which necessitates the development of biophysically relevant models
Summary
Spreading depolarization (SD) is a self-propagating wave characterized by a near-complete breakdown of transmembrane ion gradients in cells, sustained depolarization in individual neurons, and swelling of neuronal and glia cells [1, 2, 3, 4, 5]. Several clinical studies by COSBID group [15] and others suggest that SD mediates cortical lesion development and secondary brain damage in patients with acute brain injury, impairs clinical recovery, and triggers new deficits [12, 13, 3]. The neuron releases large amounts of K+ and glutamate into the extracellular space (ECS) together with significant drop in extracellular Ca2+, Na+, Cl−, and pH when it depolarizes. SD is accompanied by significant extracellular K+ and glutamate accumulation, activation of N-methyl-D-aspartate (NMDA) receptors, a general loss of ion homeostasis, and cytotoxic edema [20, 21, 22, 23, 4, 5, 24, 25, 26, 27]
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