A computational study on the role of glutamate and NMDA receptors on cortical spreading depression using a multidomain electrodiffusion model

PLoS Comput Biol. 2019 Dec 2;15(12):e1007455. doi: 10.1371/journal.pcbi.1007455. eCollection 2019 Dec.

Abstract

Cortical spreading depression (SD) is a spreading disruption of ionic homeostasis in the brain during which neurons experience complete and prolonged depolarizations. SD is the basis of migraine aura and is increasingly associated with many other brain pathologies. Here, we study the role of glutamate and NMDA receptor dynamics in the context of an ionic electrodiffusion model. We perform simulations in one (1D) and two (2D) spatial dimension. Our 1D simulations reproduce the "inverted saddle" shape of the extracellular voltage signal for the first time. Our simulations suggest that SD propagation depends on two overlapping mechanisms; one dependent on extracellular glutamate diffusion and NMDA receptors and the other dependent on extracellular potassium diffusion and persistent sodium channel conductance. In 2D simulations, we study the dynamics of spiral waves. We study the properties of the spiral waves in relation to the planar 1D wave, and also compute the energy expenditure associated with the recurrent SD spirals.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain / metabolism
  • Computational Biology
  • Computer Simulation
  • Cortical Spreading Depression / physiology*
  • Glutamic Acid / metabolism*
  • Humans
  • Ion Channels / metabolism
  • Models, Neurological*
  • Neurons / metabolism
  • Nonlinear Dynamics
  • Potassium / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Sodium Channels / metabolism

Substances

  • Ion Channels
  • Receptors, N-Methyl-D-Aspartate
  • Sodium Channels
  • Glutamic Acid
  • Potassium

Grant support

A.T. and Y.M. were supported by the National Science Foundation, grant number DMS 1516978 and J.R.D. was supported by the National Science Foundation grant number DMS 1516176. The National Science Foundation, DMS (Division of Mathematical Sciences) website is: https://www.nsf.gov/div/index.jsp?div=DMS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.