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

105 Scopus citations


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
Issue numberSUPPL. 2
StatePublished - Feb 2009


  • 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

  • Neurology
  • Clinical Neurology

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