Brain Advance Access originally published online on May 12, 2009
Brain 2009 132(6):1563-1576; doi:10.1093/brain/awp107
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Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females
1 Division of Neurology, Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA 2 Department of Neurology, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 3 Neuroscience Graduate Group, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 4 Department of Pathology, Children's Hospital of Philadelphia, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 5 Department of Human Genetics, Neurology and Pediatrics, University of Chicago, Chicago, IL, USA 6 Department of Clinical Genetics; Sophia Children's; Hospital, Erasmus Medical Center, University of Rotterdam, Rotterdam, The Netherlands 7 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA 8 Department of Pediatrics, Division of Neurology, University of Colorado, Denver School of Medicine and The Children's Hospital, Aurora CO, USA
Correspondence to: Eric Marsh, Abramson Research Center, Rm. 502, Children's Hospital of Philadelphia, 3615 Civic Center Blvd. Philadelphia, PA. 19104, USA E-mail: marshe{at}email.chop.edu
Correspondence may also be addressed to: Jeffery A. Golden, Department of Pathology, Children's Hospital of Philadelphia, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA E-mail: goldenj{at}mail.med.upenn.edu
Mutations in the X-linked aristaless-related homeobox gene (ARX) have been linked to structural brain anomalies as well as multiple neurocognitive deficits. The generation of Arx-deficient mice revealed several morphological anomalies, resembling those observed in patients and an interneuron migration defect but perinatal lethality precluded analyses of later phenotypes. Interestingly, many of the neurological phenotypes observed in patients with various ARX mutations can be attributed, in part, to interneuron dysfunction. To directly test this possibility, mice carrying a floxed Arx allele were generated and crossed to Dlx5/6CRE-IRES-GFP(Dlx5/6CIG) mice, conditionally deleting Arx from ganglionic eminence derived neurons including cortical interneurons. We now report that Arx–/y;Dlx5/6CIG (male) mice exhibit a variety of seizure types beginning in early-life, including seizures that behaviourally and electroencephalographically resembles infantile spasms, and show evolution through development. Thus, this represents a new genetic model of a malignant form of paediatric epilepsy, with some characteristics resembling infantile spasms, caused by mutations in a known infantile spasms gene. Unexpectedly, approximately half of the female mice carrying a single mutant Arx allele (Arx–/+;Dlx5/6CIG) also developed seizures. We also found that a subset of human female carriers have seizures and neurocognitive deficits. In summary, we have identified a previously unrecognized patient population with neurological deficits attributed to ARX mutations that are recapitulated in our mouse model. Furthermore, we show that perturbation of interneuron subpopulations is an important mechanism underling the pathogenesis of developmental epilepsy in both hemizygous males and carrier females. Given the frequency of ARX mutations in patients with infantile spasms and related disorders, our data unveil a new model for further understanding the pathogenesis of these disorders.
Key Words: Epilepsy; development; conditional knockout; genetic model; interneurons
Abbreviations: AR, Androgen receptor; ARX, aristaless-related homeobox gene; HP, hippocampal; XLAG, X-linked lissencephaly with abnormal genitalia
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Received November 25, 2008. Revised February 27, 2009. Accepted March 19, 2009.
*These authors contributed equally to this work.
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