Neonatal estradiol stimulation prevents epilepsy in Arx model of X-linked infantile spasms syndrome

Sci Transl Med. 2014 Jan 22;6(220):220ra12. doi: 10.1126/scitranslmed.3007231.


Infantile spasms are a catastrophic form of pediatric epilepsy with inadequate treatment. In patients, mutation of ARX, a transcription factor selectively expressed in neuronal precursors and adult inhibitory interneurons, impairs cell migration and causes a major inherited subtype of the disease X-linked infantile spasms syndrome. Using an animal model, the Arx((GCG)10+7) mouse, we determined that brief estradiol (E2) administration during early postnatal development prevented spasms in infancy and seizures in adult mutants. E2 was ineffective when delivered after puberty or 30 days after birth. Early E2 treatment altered mRNA levels of three downstream targets of Arx (Shox2, Ebf3, and Lgi1) and restored depleted interneuron populations without increasing GABAergic synaptic density. Postnatal E2 treatment may induce lasting transcriptional changes that lead to enduring disease modification and could potentially serve as a therapy for inherited interneuronopathies.

Publication types

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

MeSH terms

  • Aicardi Syndrome / drug therapy*
  • Animals
  • Anticonvulsants / therapeutic use
  • Disease Models, Animal
  • Electroencephalography
  • Epilepsy / prevention & control*
  • Estradiol / therapeutic use*
  • Estrogen Receptor alpha / agonists
  • Estrogen Receptor beta / agonists
  • Homeodomain Proteins / genetics*
  • Interneurons / drug effects
  • Male
  • Mice
  • Mutation
  • Neurons / metabolism
  • Phenotype
  • Spasm / prevention & control
  • Spasms, Infantile / drug therapy*
  • Transcription Factors / genetics*
  • Transcription, Genetic


  • ARX protein, mouse
  • Anticonvulsants
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Homeodomain Proteins
  • Transcription Factors
  • Estradiol

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy