Key Event Title
Key Event Component
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures||KeyEvent|
Level of Biological Organization
How This Key Event Works
A paroxysmal depolarizing shift (PDS) or depolarizing shift is a cellular manifestation of epilepsy. As summarized by Lomen-Hoerth and Messing (2010), brain electrical activity is non synchronous under normal conditions. In epileptic seizures, a large group of neurons begin firing in an abnormal, excessive, and synchronized manner, which results in a wave of depolarization known as a paroxysmal depolarizing shift (Somjen, 2004). Normally after an excitatory neuron fires it becomes more resistant to firing for a period of time, owing in part to the effect of inhibitory neurons, electrical changes within the excitatory neuron, and the negative effects of adenosine. However, in epilepsy the resistance of excitatory neurons to fire during this period is decreased, likely due to changes in ion channels or inhibitory neurons not functioning properly. This then results in a specific area from which seizures may develop, known as a "seizure focus".
Increased, abnormal neuron firing causes a wave of depolarization throughout the brain/neuronal tissue. At the level of single neurons, epileptiform activity consists of sustained neuronal depolarization resulting in a burst of action potentials, a plateau-like depolarization associated with completion of the action potential burst, and then a rapid repolarization followed by hyperpolarization. This sequence is called the paroxysmal depolarizing shift (PDS). The bursting activity resulting from the relatively prolonged depolarization of the neuronal membrane is due to influx of extracellular Ca2+, which leads to the opening of voltage-dependent Na+ channels, influx of Na+, and generation of repetitive action potentials. The subsequent hyperpolarizing afterpotential is mediated by iGABA receptors and Cl- influx, or by K+ efflux, depending on the cell type (Bromfield et al 2006).
How It Is Measured or Detected
Paroxysmal depolarizing shifts can be measured in vitro using patch clamp methods or in vivo using electroencephalography techniques (Niedermeyer and da Silva 2005).
Evidence Supporting Taxonomic Applicability
Most of the supporting evidence come from studies on human and rodents. See the reviews of Bromfield (2006) and Lomen-Hoerth and Messing (2010) for examples.
Bromfield EB, Cavazos JE, Sirven JI. 2006. An Introduction to Epilepsy [Internet]. West Hartford (CT): American Epilepsy Society; Chapter 1, Basic Mechanisms Underlying Seizures and Epilepsy. Available from: http://www.ncbi.nlm.nih.gov/books/NBK2510/.
Lomen-Hoerth C, Messing RO. 2010. Chapter 7: Nervous system disorders. Edited by Stephen J. McPhee, and Gary D. Hammer, Pathophysiology of disease: an introduction to clinical medicine (6th Edition). New York: McGraw-Hill Medical. ISBN 9780071621670.
Niedermeyer E, da Silva FL. 2005. Electroencephalography: basic principles, clinical applications, and related fields. Lippincott Williams & Wilkins.
Somjen GG. 2004. Ions in the Brain Normal Function, Seizures, and Stroke. New York: Oxford University Press. p. 167.