Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement

Nat Commun. 2016 Jun 1;7:11753. doi: 10.1038/ncomms11753.

Abstract

Focal cortical dysplasia (FCD), a local malformation of cortical development, is the most common cause of pharmacoresistant epilepsy associated with life-long neurocognitive impairments. It remains unclear whether neuronal misplacement is required for seizure activity. Here we show that dyslamination and white matter heterotopia are not necessary for seizure generation in a murine model of type II FCDs. These experimental FCDs generated by increasing mTOR activity in layer 2/3 neurons of the medial prefrontal cortex are associated with tonic-clonic seizures and a normal survival rate. Preventing all FCD-related defects, including neuronal misplacement and dysmorphogenesis, with rapamycin treatments from birth eliminates seizures, but seizures recur after rapamycin withdrawal. In addition, bypassing neuronal misplacement and heterotopia using inducible vectors do not prevent seizure occurrence. Collectively, data obtained using our new experimental FCD-associated epilepsy suggest that life-long treatment to reduce neuronal dysmorphogenesis is required to suppress seizures in individuals with FCD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Male
  • Malformations of Cortical Development / drug therapy*
  • Malformations of Cortical Development / genetics
  • Malformations of Cortical Development / metabolism
  • Malformations of Cortical Development / pathology
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology
  • Seizures / drug therapy*
  • Seizures / genetics
  • Seizures / metabolism
  • Seizures / pathology
  • Signal Transduction
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism
  • White Matter / drug effects
  • White Matter / metabolism
  • White Matter / pathology

Substances

  • Green Fluorescent Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus