An epilepsy-related ARX polyalanine expansion modifies glutamatergic neurons excitability and morphology without affecting GABAergic neurons development

Cereb Cortex. 2013 Jun;23(6):1484-94. doi: 10.1093/cercor/bhs138. Epub 2012 May 24.


Epileptic encephalopathies comprise a heterogeneous group of severe infantile disorders for which the pathophysiological basis of epilepsy is inaccurately clarified by genotype-phenotype analysis. Because a deficit of GABA neurons has been found in some of these syndromes, notably in patients with X-linked lissencephaly with abnormal genitalia, epilepsy was suggested to result from an imbalance in GABAergic inhibition, and the notion of "interneuronopathy" was proposed. Here, we studied the impact of a polyalanine expansion of aristaless-related homeobox (ARX) gene, a mutation notably found in West and Ohtahara syndromes. Analysis of Arx((GCG)7/Y) knock-in mice revealed that GABA neuron development is not affected. Moreover, pyramidal cell migration and cortical layering are unaltered in these mice. Interestingly, electrophysiological recordings show that hippocampal pyramidal neurons displayed a frequency of inhibitory postsynaptic currents similar to wild-type (WT) mice. However, these neurons show a dramatic increase in the frequency of excitatory inputs associated with a remodeling of their axonal arborization, suggesting that epilepsy in Arx((GCG)7/Y)mice would result from a glutamate network remodeling. We therefore propose that secondary alterations are instrumental for the development of disease-specific phenotypes and should be considered to explain the phenotypic diversity associated with epileptogenic mutations.

Keywords: ARX; epilepsy; network excitability; neuronal migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Age Factors
  • Animals
  • Animals, Newborn
  • Cell Movement / genetics
  • Electroporation
  • Embryo, Mammalian
  • Excitatory Amino Acid Antagonists / pharmacology
  • Female
  • GABAergic Neurons / cytology
  • GABAergic Neurons / physiology*
  • Gene Expression Regulation, Developmental / genetics*
  • Glutamate Decarboxylase / metabolism
  • Glutamates / metabolism*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Homeodomain Proteins / genetics*
  • Humans
  • Lysine / analogs & derivatives
  • Lysine / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Peptides / genetics*
  • RNA, Small Interfering / genetics
  • Statistics, Nonparametric
  • Synaptic Potentials / drug effects
  • Synaptic Potentials / genetics
  • Transcription Factors / genetics*
  • Transfection
  • gamma-Aminobutyric Acid / metabolism*


  • ARX protein, human
  • Excitatory Amino Acid Antagonists
  • Glutamates
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Peptides
  • RNA, Small Interfering
  • Transcription Factors
  • Green Fluorescent Proteins
  • polyalanine
  • gamma-Aminobutyric Acid
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • biocytin
  • Lysine