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

ABSTRACT: 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.

SUBMITTER: Olivetti PR

PROVIDER: S-EPMC4034383 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Olivetti Pedro R PR Maheshwari Atul A Noebels Jeffrey L JL

Science translational medicine 20140101 220

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 ...[more]

PMID: 24452264

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Project description:X-linked infantile spasms syndrome (ISSX) is a clinically devastating developmental epileptic encephalopathy with life-long impact. Arx(GCG)10+7 , a mouse model of the most common triplet-repeat expansion mutation of ARX, exhibits neonatal spasms, electrographic phenotypes and abnormal migration of GABAergic interneuron subtypes. Neonatal presymptomatic treatment with 17β-estradiol (E2) in Arx(GCG)10+7 reduces spasms and modifies progression of epilepsy. Cortical pathology during this period, a crucial point for clinical intervention in ISSX, has largely been unexplored, and the pathogenic cellular defects that are targeted by early interventions are unknown. In the first postnatal week, we identified a transient wave of elevated apoptosis in Arx(GCG)10+7 mouse cortex that is non-Arx cell autonomous, since mutant Arx-immunoreactive (Arx+) cells are not preferentially impacted by cell death. NeuN+ (also known as Rbfox3) survival was also not impacted, suggesting a vulnerable subpopulation in the immature Arx(GCG)10+7 cortex. Inflammatory processes during this period might explain this transient elevation in apoptosis; however, transcriptomic and immunohistochemical profiling of several markers of inflammation revealed no innate immune activation in Arx(GCG)10+7 cortex. Neither neonatal E2 hormone therapy, nor ACTH(1-24), the frontline clinical therapy for ISSX, diminished the augmented apoptosis in Arx(GCG)10+7 , but both rescued neocortical Arx+ cell density. Since early E2 treatment effectively prevents seizures in this model, enhanced apoptosis does not solely account for the seizure phenotype, but may contribute to other aberrant brain function in ISSX. However, since both hormone therapies, E2 and ACTH(1-24), elevate the density of cortical Arx+-interneurons, their early therapeutic role in other neurological disorders hallmarked by interneuronopathy should be explored.This article has an associated First Person interview with the first author of the paper.

Project description:ObjectiveInfantile spasms (IS) is a severe epilepsy in early childhood. Early treatment of IS provides the best chance of seizure remission and favorable developmental outcome. We aimed to develop a prediction rule to accurately predict which neonates with acute symptomatic seizures will develop IS.MethodsWe used data from the Neonatal Seizure Registry, a prospective, multicenter cohort of infants with acute symptomatic neonatal seizures born from July 2015 to March 2018. Neonates with acute symptomatic seizures who received clinical electroencephalography (EEG) and magnetic resonance imaging (MRI) and were younger than 2 years of age at the time of enrollment were included. We evaluated the association of neonatal EEG, MRI, and clinical factors with subsequent IS using bivariate analysis and best subsets logistic regression. We selected a final model through a consensus process that balanced statistical significance with clinical relevance.ResultsIS developed in 12 of 204 infants (6%). Multiple potential predictors were associated with IS, including Apgar scores, EEG features, seizure characteristics, MRI abnormalities, and clinical status at hospital discharge. The final model included three risk factors: (a) severely abnormal EEG or ≥3 days with seizures recorded on EEG, (b) deep gray or brainstem injury on MRI, and (c) abnormal tone on discharge exam. The stratified risk of IS was the following: no factors 0% (0/82, 95% confidence interval [CI] 0%-4%), one or two factors 4% (4/108, 95% CI 1%-9%), and all three factors 57% (8/14, 95% CI 29%-83%).SignificanceIS risk after acute symptomatic neonatal seizures can be stratified using commonly available clinical data. No child without risk factors, vs >50% of those with all three factors, developed IS. This risk prediction rule may be valuable for clinical counseling as well as for selecting participants for clinical trials to prevent post-neonatal epilepsy. This tailored approach may lead to earlier diagnosis and treatment and improve outcomes for a devastating early life epilepsy.

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

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

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