Epilepsy following cortical injury: Cellular and molecular mechanisms as targets for potential prophylaxis

David A. Prince, Isabel Parada, Karina Scalise, Kevin Graber, Xiaoming Jin, Fran Shen

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

The sequelae of traumatic brain injury, including posttraumatic epilepsy, represent a major societal problem. Significant resources are required to develop a better understanding of the underlying pathophysiologic mechanisms as targets for potential prophylactic therapies. Posttraumatic epilepsy undoubtedly involves numerous pathogenic factors that develop more or less in parallel. We have highlighted two potential "prime movers": disinhibition and development of new functional excitatory connectivity, which occur in a number of animal models and some forms of epilepsy in humans. Previous experiments have shown that tetrodotoxin (TTX) applied to injured cortex during a critical period early after lesion placement can prevent epileptogenesis in the partial cortical ("undercut") model of posttraumatic epilepsy. Here we show that such treatment markedly attenuates histologic indices of axonal and terminal sprouting and presumably associated aberrant excitatory connectivity. A second finding in the undercut model is a decrease in spontaneous inhibitory events. Current experiments show that this is accompanied by regressive alterations in fast-spiking γ-aminobutyric acid (GABA)ergic interneurons, including shrinkage of dendrites, marked decreases in axonal length, structural changes in inhibitory boutons, and loss of inhibitory synapses on pyramidal cells. Other data support the hypothesis that these anatomic abnormalities may result from loss of trophic support normally provided to interneurons by brain-derived neurotrophic factor (BDNF). Approaches that prevent these two pathophysiologic mechanisms may offer avenues for prophylaxis for posttraumatic epilepsy. However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans need to be resolved.

Original languageEnglish (US)
Pages (from-to)30-40
Number of pages11
JournalEpilepsia
Volume50
Issue numberSUPPL. 2
DOIs
StatePublished - Feb 2009
Externally publishedYes

Fingerprint

Epilepsy
Wounds and Injuries
Interneurons
Aminobutyrates
Pyramidal Cells
Brain-Derived Neurotrophic Factor
Tetrodotoxin
Dendrites
Synapses
gamma-Aminobutyric Acid
Animal Models
Therapeutics

Keywords

  • Brain-derived neurotrophic factor
  • Caged glutamate
  • Cortical isolation
  • Fast-spiking
  • GAP43
  • Interneurons
  • Laser uncaging
  • Neurofilaments
  • Posttraumatic epilepsy
  • Sprouting
  • Tetrodotoxin
  • TrkB
  • Undercut

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Epilepsy following cortical injury : Cellular and molecular mechanisms as targets for potential prophylaxis. / Prince, David A.; Parada, Isabel; Scalise, Karina; Graber, Kevin; Jin, Xiaoming; Shen, Fran.

In: Epilepsia, Vol. 50, No. SUPPL. 2, 02.2009, p. 30-40.

Research output: Contribution to journalArticle

Prince, David A. ; Parada, Isabel ; Scalise, Karina ; Graber, Kevin ; Jin, Xiaoming ; Shen, Fran. / Epilepsy following cortical injury : Cellular and molecular mechanisms as targets for potential prophylaxis. In: Epilepsia. 2009 ; Vol. 50, No. SUPPL. 2. pp. 30-40.
@article{cf326ad98c804675acce7288fd517a1d,
title = "Epilepsy following cortical injury: Cellular and molecular mechanisms as targets for potential prophylaxis",
abstract = "The sequelae of traumatic brain injury, including posttraumatic epilepsy, represent a major societal problem. Significant resources are required to develop a better understanding of the underlying pathophysiologic mechanisms as targets for potential prophylactic therapies. Posttraumatic epilepsy undoubtedly involves numerous pathogenic factors that develop more or less in parallel. We have highlighted two potential {"}prime movers{"}: disinhibition and development of new functional excitatory connectivity, which occur in a number of animal models and some forms of epilepsy in humans. Previous experiments have shown that tetrodotoxin (TTX) applied to injured cortex during a critical period early after lesion placement can prevent epileptogenesis in the partial cortical ({"}undercut{"}) model of posttraumatic epilepsy. Here we show that such treatment markedly attenuates histologic indices of axonal and terminal sprouting and presumably associated aberrant excitatory connectivity. A second finding in the undercut model is a decrease in spontaneous inhibitory events. Current experiments show that this is accompanied by regressive alterations in fast-spiking γ-aminobutyric acid (GABA)ergic interneurons, including shrinkage of dendrites, marked decreases in axonal length, structural changes in inhibitory boutons, and loss of inhibitory synapses on pyramidal cells. Other data support the hypothesis that these anatomic abnormalities may result from loss of trophic support normally provided to interneurons by brain-derived neurotrophic factor (BDNF). Approaches that prevent these two pathophysiologic mechanisms may offer avenues for prophylaxis for posttraumatic epilepsy. However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans need to be resolved.",
keywords = "Brain-derived neurotrophic factor, Caged glutamate, Cortical isolation, Fast-spiking, GAP43, Interneurons, Laser uncaging, Neurofilaments, Posttraumatic epilepsy, Sprouting, Tetrodotoxin, TrkB, Undercut",
author = "Prince, {David A.} and Isabel Parada and Karina Scalise and Kevin Graber and Xiaoming Jin and Fran Shen",
year = "2009",
month = "2",
doi = "10.1111/j.1528-1167.2008.02008.x",
language = "English (US)",
volume = "50",
pages = "30--40",
journal = "Epilepsia",
issn = "0013-9580",
publisher = "Wiley-Blackwell",
number = "SUPPL. 2",

}

TY - JOUR

T1 - Epilepsy following cortical injury

T2 - Cellular and molecular mechanisms as targets for potential prophylaxis

AU - Prince, David A.

AU - Parada, Isabel

AU - Scalise, Karina

AU - Graber, Kevin

AU - Jin, Xiaoming

AU - Shen, Fran

PY - 2009/2

Y1 - 2009/2

N2 - The sequelae of traumatic brain injury, including posttraumatic epilepsy, represent a major societal problem. Significant resources are required to develop a better understanding of the underlying pathophysiologic mechanisms as targets for potential prophylactic therapies. Posttraumatic epilepsy undoubtedly involves numerous pathogenic factors that develop more or less in parallel. We have highlighted two potential "prime movers": disinhibition and development of new functional excitatory connectivity, which occur in a number of animal models and some forms of epilepsy in humans. Previous experiments have shown that tetrodotoxin (TTX) applied to injured cortex during a critical period early after lesion placement can prevent epileptogenesis in the partial cortical ("undercut") model of posttraumatic epilepsy. Here we show that such treatment markedly attenuates histologic indices of axonal and terminal sprouting and presumably associated aberrant excitatory connectivity. A second finding in the undercut model is a decrease in spontaneous inhibitory events. Current experiments show that this is accompanied by regressive alterations in fast-spiking γ-aminobutyric acid (GABA)ergic interneurons, including shrinkage of dendrites, marked decreases in axonal length, structural changes in inhibitory boutons, and loss of inhibitory synapses on pyramidal cells. Other data support the hypothesis that these anatomic abnormalities may result from loss of trophic support normally provided to interneurons by brain-derived neurotrophic factor (BDNF). Approaches that prevent these two pathophysiologic mechanisms may offer avenues for prophylaxis for posttraumatic epilepsy. However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans need to be resolved.

AB - The sequelae of traumatic brain injury, including posttraumatic epilepsy, represent a major societal problem. Significant resources are required to develop a better understanding of the underlying pathophysiologic mechanisms as targets for potential prophylactic therapies. Posttraumatic epilepsy undoubtedly involves numerous pathogenic factors that develop more or less in parallel. We have highlighted two potential "prime movers": disinhibition and development of new functional excitatory connectivity, which occur in a number of animal models and some forms of epilepsy in humans. Previous experiments have shown that tetrodotoxin (TTX) applied to injured cortex during a critical period early after lesion placement can prevent epileptogenesis in the partial cortical ("undercut") model of posttraumatic epilepsy. Here we show that such treatment markedly attenuates histologic indices of axonal and terminal sprouting and presumably associated aberrant excitatory connectivity. A second finding in the undercut model is a decrease in spontaneous inhibitory events. Current experiments show that this is accompanied by regressive alterations in fast-spiking γ-aminobutyric acid (GABA)ergic interneurons, including shrinkage of dendrites, marked decreases in axonal length, structural changes in inhibitory boutons, and loss of inhibitory synapses on pyramidal cells. Other data support the hypothesis that these anatomic abnormalities may result from loss of trophic support normally provided to interneurons by brain-derived neurotrophic factor (BDNF). Approaches that prevent these two pathophysiologic mechanisms may offer avenues for prophylaxis for posttraumatic epilepsy. However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans need to be resolved.

KW - Brain-derived neurotrophic factor

KW - Caged glutamate

KW - Cortical isolation

KW - Fast-spiking

KW - GAP43

KW - Interneurons

KW - Laser uncaging

KW - Neurofilaments

KW - Posttraumatic epilepsy

KW - Sprouting

KW - Tetrodotoxin

KW - TrkB

KW - Undercut

UR - http://www.scopus.com/inward/record.url?scp=58849163104&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58849163104&partnerID=8YFLogxK

U2 - 10.1111/j.1528-1167.2008.02008.x

DO - 10.1111/j.1528-1167.2008.02008.x

M3 - Article

C2 - 19187292

AN - SCOPUS:58849163104

VL - 50

SP - 30

EP - 40

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - SUPPL. 2

ER -