API

Event: 616

Key Event Title

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Occurrence, A paroxysmal depolarizing shift

Short name

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Occurrence, A paroxysmal depolarizing shift

Biological Context

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Level of Biological Organization
Tissue


Organ term

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Organ term
brain


Key Event Components

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Process Object Action
membrane depolarization occurrence

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Blocking iGABA receptor ion channel leading to seizures KeyEvent

Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI

Life Stages

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Life stage Evidence
Adult High

Sex Applicability

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Term Evidence
Unspecific High

Key Event Description

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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 also called 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

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Paroxysmal depolarizing shifts can be measured in vitro using patch-clamp recording technique (Kapur 2009) or micro-electrode arrays (Novellino et al. 2011) to determin effects of chemicals on action potential patterns of neurons.

PDS can be detected in vivo using electroencephalography techniques (Niedermeyer and da Silva 2005).


Domain of Applicability

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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.


References

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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/.

Kapur J. 2009. GABA | Pathophysiology of Status Epilepticus. Encyclopedia of Basic Epilepsy Research, pp 304-8.

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.

Novellino A, Scelfo B, Palosaari T, Price A, Sobanski T, Shafer TJ, Johnstone AF, Gross GW, Gramowski A, Schroeder O, Jügelt K, Chiappalone M, Benfenati F, Martinoia S, Tedesco MT, Defranchi E, D'Angelo P, Whelan M. 2011. Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals. Front Neuroeng. 4:4.

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.