Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations

Cereb Cortex. 2015 Sep;25(9):2939-50. doi: 10.1093/cercor/bhu090. Epub 2014 May 2.


Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses.

Keywords: anxiety; hyperactivity; learning; mouse; socialization.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain Waves / genetics*
  • Choice Behavior / physiology
  • Conditioning, Psychological / physiology
  • Dark Adaptation / genetics
  • Developmental Disabilities / genetics
  • Disease Models, Animal
  • Epilepsy / genetics
  • Exploratory Behavior / physiology
  • Gene Expression Regulation, Developmental / genetics
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism*
  • Humans
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / genetics
  • Muscle Strength / genetics
  • Mutation / genetics*
  • Phenotype
  • Smell / genetics
  • Telencephalon / growth & development*
  • Telencephalon / metabolism*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*


  • ARX protein, human
  • Homeodomain Proteins
  • Transcription Factors