Oxygen and Seizure Dynamics: II. Computational Modeling

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hippocampus, hypoxia, bifurcation, epilepsy, potassium

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Electrophysiological recordings show intense neuronal firing during epileptic seizures leading to enhanced energy consumption. However, the relationship between oxygen metabolism and seizure patterns has not been well studied. Recent studies have developed fast and quantitative techniques to measure oxygen microdomain concentration during seizure events. In this article, we develop a biophysical model that accounts for these experimental observations. The model is an extension of the Hodgkin-Huxley formalism and includes the neuronal microenvironment dynamics of sodium, potassium, and oxygen concentrations. Our model accounts for metabolic energy consumption during and following seizure events. We can further account for the experimental observation that hypoxia can induce seizures, with seizures occurring only within a narrow range of tissue oxygen pressure. We also reproduce the interplay between excitatory and inhibitory neurons seen in experiments, accounting for the different oxygen levels observed during seizures in excitatory vs. inhibitory cell layers. Our findings offer a more comprehensive understanding of the complex interrelationship among seizures, ion dynamics, and energy metabolism.

the brain consumes 20% of the body's metabolic energy with muscles and digestive system at rest, despite being only 2% of the human body mass (Attwell and Laughlin 2001). The majority of the brain's metabolic energy is dedicated to supporting neural spiking activity, most of which is used by Na+-K+-ATP pumps that transport 3Na+ outwards with 2K+ inwards against their concentration gradients (Erecińska and Dagani 1990; Attwell and Laughlin 2001; Lennie 2003). Oxygen is an essential element for brain activity due to its central role in producing adenosine triphosphate (ATP). A complete lack of oxygen will result in the death of brain cells within tens of minutes (Hochachka and Guppy 1987).

The delicate balance between energy supply and expenditure becomes critically strained in pathological brain activity such as seizures and spreading depression, during which excessive O2 demands transiently exceeded O2 supply (Bahar et al. 2006; Galeffi et al. 2011). Although such oxygen changes with high levels of neural activity are well known, and patterns of damage to selectively vulnerable areas of the brain well characterized (such as Sommer's sector in the hippocampus, see Aitken and Schiff 1986), the methodology to examine rapid oxygen changes at small spatiotemporal scales has only become recently available (Koo et al. 2004; Bahar et al. 2006). To improve the spatiotemporal limitations of O2 sensing, we designed a ratiometric nano quantum dot (NQD) fluorescence resonance energy transfer (FRET) excited optical sensor to rapidly measure interstitial oxygen quantitatively from single cell microdomains to an entire hippocampal slice with high spatiotemporal resolution (Ingram et al. 2013). In a companion article (Ingram et al. 2014), we used this and related technologies to perform experiments relating seizure activity at the cellular level with simultaneous real-time oxygen microdomain measurements.

To better understand the relationship between seizures and oxygen dynamics, we here construct a biophysical model to account for experimental observations. We extend the Hodgkin-Huxley formalism by including the dynamics of Na+ and K+ ion concentrations as well as oxygen homeostasis. These ion concentrations are coupled to Na+-K+-ATP pump activity, a simplified glia-endothelium system, and diffusive transport from either the bath solution in a slice preparation, or the vasculature in the intact brain (Cressman et al. 2009; Ullah et al. 2009; Ullah and Schiff 2009 2010). We focus on energy consumed by Na+-K+-ATP pump activity, because most of the energy expenditure in active neurons is due to restoring ion gradients (Lennie 2003). We here demonstrate that a computational model incorporating basic features of oxygen metabolism can account for the broader spectrum of experimental observations including differential oxygen consumption between layers in the hippocampus, the delays to restore the O2 deficit after intense activity, the mechanisms contributing to excitatory-inhibitory cell interplay, and how seizures can be supported only within a narrow range of tissue oxygen concentration (companion article, Ingram et al. 2014). Our work suggests the critical importance of modeling extracellular ion concentration and oxygen dynamics to properly understand the underlying mechanisms behind seizures and related phenomena.

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Citation / Publisher Attribution

Journal of Neurophysiology, v. 112, issue 2, p. 213-223