Neonatal estradiol stimulation prevents epilepsy in Arx model of X-linked infantile spasms syndrome.
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.
Blue Bird Circle Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
Pedro R
PR
Olivetti
Atul
A
Maheshwari
Jeffrey L
JL
Noebels
D058540:Aicardi Syndrome / Q000188:drug therapy*; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000517:prevention & control*; D004958:Estradiol / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000819:agonists; D047629:Estrogen Receptor beta / Q000819:agonists; D018398:Homeodomain Proteins / Q000235:genetics*; D007395:Interneurons / Q000187:drug effects; D008297:Male; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D013035:Spasm / Q000517:prevention & control; D013036:Spasms, Infantile / Q000188:drug therapy*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
C469265:ARX protein, mouse; D000927:Anticonvulsants; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018398:Homeodomain Proteins; D014157:Transcription Factors; D004958:Estradiol