Female hormones prevent a catastrophic epilepsy in male mice.

Commentary Infantile spasms (IS) is a catastrophic epilepsy syndrome occurring during the specific developmental period of infancy and early childhood. In addition to the stereotypic motor spasms, patients with IS typically develop long-term intellectual disability and other seizure types that are often resistant to treatment. A variety of acquired brain injuries at this critical age can result in IS, such as hypoxia–ischemia, meningitis, and traumatic brain injury. However, with advances in genetic testing, an increasing number of genetic mutations have been identified as etiologies of IS (1). An X-linked recessive IS syndrome has recently been described in association with mutations in the Aristaless-related homeobox (ARX) gene (2). ARX mutations have also been implicated in causing a spectrum of related neurologi-cal disorders primarily affecting males, including X-linked lissencephaly with abnormal genitalia, Partington syndrome (intellectual disability with focal dystonia), and nonsyndromic mental retardation (3). The ARX protein is a transcriptional factor that modulates the expression of a number of other genes involved in migration and differentiation of interneurons. Thus, ARX mutations most likely cause IS due to migration defects of cortical and subcortical interneurons. To investigate the pathophysiological mechanisms of ARX mutations in more detail, a number of mouse models have been created. A conventional knockout mouse involving constitutive inactivation of the Arx gene in all cells dies shortly after birth but exhibits a small, malformed brain with a severe interneuron migration defect, confirming the critical involvement of ARX in cortical interneuron development (4). Another model, Arx (GCG)10+7 mice, incorporates the most common human ARX mutation causing X-linked IS syndrome, a triplet repeat polyalanine expansion in the ARX gene (5). This mouse model survives into adulthood and recapitulates a number of the phenotypic features of X-linked IS syndrome, including spasm-like seizures as pups and other severe seizures and cognitive impairment as adults. In addition, Arx (GCG)10+7 mice exhibit selective reduction of specific interneuron subtypes in cortex, hippocampus, and striatum. This realistic ARX mouse model of X-linked IS syndrome provides the opportunity to identify downstream mechanisms involved in generating the phenotype and to assess rational, mechanistically targeted treatments for this disorder. Given the evidence of neuronal migration defects related to ARX mutations, one testable hypothesis involves hormonal regulation of cortical development. In particular, surges in estrogen—mediated by local conversion of testosterone in the male brain—and associated estrogen receptor expression during critical developmental stages have been implicated in promoting cortical development, including migration of …