Large extracellular space leads to neuronal susceptibility to ischemic injury in a Na+/K + pumps–dependent manner
- 490 Downloads
The extent of anoxic depolarization (AD), the initial electrophysiological event during ischemia, determines the degree of brain region–specific neuronal damage. Neurons in higher brain regions exhibiting nonreversible, strong AD are more susceptible to ischemic injury as compared to cells in lower brain regions that exhibit reversible, weak AD. While the contrasting ADs in different brain regions in response to oxygen–glucose deprivation (OGD) is well established, the mechanism leading to such differences is not clear. Here we use computational modeling to elucidate the mechanism behind the brain region–specific recovery from AD. Our extended Hodgkin–Huxley (HH) framework consisting of neural spiking dynamics, processes of ion accumulation, and ion homeostatic mechanisms unveils that glial–vascular K+ clearance and Na+/K+–exchange pumps are key to the cell’s recovery from AD. Our phase space analysis reveals that the large extracellular space in the upper brain regions leads to impaired Na+/K+–exchange pumps so that they function at lower than normal capacity and are unable to bring the cell out of AD after oxygen and glucose is restored.
KeywordsAnoxic depolarization Extracellular volume Hodgkin–Huxley Ion dynamics Neural mircoenvironment Brain injury
This study was supported by a startup grant from College of Arts and Sciences awarded to Ghanim Ullah.
Compliance with Ethical Standards
Conflict of interests
The authors declare that they have no conflict of interest.
- Blanco, G. (2005). Na,k–ATPase subunit heterogeneity as a mechanism for tissue-specific ion regulation. In Seminars in nephrology, vol. 25, pp. 292–303: Elsevier.Google Scholar
- Brisson, C.D., Hsieh, Y.T., Kim, D., Jin, A.Y., & Andrew, R.D. (2014). Brainstem neurons survive the identical ischemic stress that kills higher neurons: insight to the persistent vegetative state. PloS one, 9(5).Google Scholar
- Cressman Jr., J.R., Ullah, G., Ziburkus, J., Schiff, S.J., & Barreto, E. (2009). The influence of sodium and potassium dynamics on excitability, seizures, and the stability of persistent states: I. single neuron dynamics. Journal of Computational Neuroscience, 26, 159–170.CrossRefPubMedPubMedCentralGoogle Scholar
- Cressman Jr., J.R., Ullah, G., Ziburkus, J., Schiff, S.J., & Barreto, E. (2011). Erratum to: The influence of sodium and potassium dynamics on excitability, seizures, and the stability of persistent states: I. single neuron dynamics. Journal of Computational Neuroscience, 30, 781.CrossRefGoogle Scholar
- Doedel, E.J., & Oldeman, B.E. (2009). Auto-07p: Continuation and bifurcation software for ordinary differential equations. Montreal: Concordia University.Google Scholar
- Fröhlich, F., & Bazhenov, M. (2006). Coexistence of tonic firing and bursting in cortical neurons. Physical Review E, 74(031922).Google Scholar
- Hoffmann, U., Sukhotinsky, I., Atalay, Y.B., Eikermann-Haerter, K., & Ayata, C. (2012). Increased glucose availability does not restore prolonged spreading depression durations in hypotensive rats without brain injury. Experimental Neurology, 238(2), 130–132.CrossRefPubMedPubMedCentralGoogle Scholar
- Lauderdale, K., Murphy, T., Tung, T., Davila, D., Binder, D.K., & Fiacco, T.A. (2015). Osmotic edema rapidly increases neuronal excitability through activation of NMDA receptor–dependent slow inward currents in juvenile and adult hippocampus. ASN Neuro, 7(5), 1759091415605,115. doi: 10.1177/1759091415605115.CrossRefGoogle Scholar
- Murphy, T.H., Li, P., Betts, K., & Liu, R. (2008). Two-photon imaging of stroke onset in vivo reveals that nmda-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines. The Journal of Neuroscience, 28(7), 1756–1772.CrossRefPubMedGoogle Scholar
- Somjen, G.G. (2004). Ions in the brain: normal function, seizures, and stroke. USA: Oxford University Press.Google Scholar
- Sukhotinsky, I., Yaseen, M.A., Sakadžić, S., Ruvinskaya, S., Sims, J.R., Boas, D.A., Moskowitz, M.A., & Ayata, C. (2010). Perfusion pressure–dependent recovery of cortical spreading depression is independent of tissue oxygenation over a wide physiologic range. Journal of Cerebral Blood Flow and Metabolism, 30(6), 1168–1177. doi: 10.1038/jcbfm.2009.285.CrossRefPubMedPubMedCentralGoogle Scholar
- Xie, L., Kang, H., Xu, Q., Chen, M.J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D.J., Nicholson, C., Iliff, J.J., Takano, K., Deane, R., & Nedergaard, M. (2013). Sleep drives metabolite clearance from the adult brain. Science, 342(6156), 373–377. doi: 10.1126/science.1241224.CrossRefPubMedGoogle Scholar
- Zamecnik, J., Homola, A., Cicanic, M., Kuncova, K., Marusic, P., Krsek, P., Syková, E., & Vargova, L. (2012). The extracellular matrix and diffusion barriers in focal cortical dysplasias. European Journal of Neuroscience, 36, 2017–2024. doi: 10.1111/j.1460-9568.2012.08107.x.CrossRefPubMedGoogle Scholar