Conditions for the triggering of spreading depression studied with computer simulations.

Area of Science:

• Neuroscience
• Computational Biology
• Biophysics

Background:

• Spreading depression (SD) biophysics remains incompletely understood despite extensive study.
• Previous models have explored seizures and SD, suggesting ion channel currents can generate SD-like depolarization.

Purpose of the Study:

• To define conditions for triggering SD and parameters influencing its course.
• To model a hippocampal pyramidal cell with a detailed representation of ions and channels.

Main Methods:

• Developed a computational model of a hippocampal pyramidal cell with extensive ion channel representation.
• Included "leak" conductances, voltage-dependent conductances, an ion pump, and an extracellular ion regulation system.
• Simulated ion fluxes, concentration changes, osmotic volume changes, and hypoxia.

Main Results:

• Reduced glial uptake of K+ leads to interstitial accumulation, triggering SD-like depolarization.
• SD ignition occurs when apical dendrite depolarization activates persistent Na+ and NMDA-controlled currents.
• SD onset is influenced by stimulating current and glial leak conductance, but depolarization amplitude is not.

Conclusions:

• SD, once ignited, follows an all-or-none trajectory.
• Depolarization levels are governed by feedback involving ion shifts and glutamate, not solely channel number.
• SD is ignited by inward net persistent membrane current in apical dendrites.