title: An epilepsy-related ARX polyalanine expansion modifies glutamatergic neurons excitability and morphology without affecting GABAergic neurons development.
abstract: 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.
authors.affiliation: INSERM Unité 901, Marseille 13009, France.
authors.forename: Shirley
authors.initials: S
authors.lastname: Beguin
authors.forename: Valérie
authors.initials: V
authors.lastname: Crépel
authors.forename: Laurent
authors.initials: L
authors.lastname: Aniksztejn
authors.forename: Hélène
authors.initials: H
authors.lastname: Becq
authors.forename: Barbara
authors.initials: B
authors.lastname: Pelosi
authors.forename: Emilie
authors.initials: E
authors.lastname: Pallesi-Pocachard
authors.forename: Lamine
authors.initials: L
authors.lastname: Bouamrane
authors.forename: Massimo
authors.initials: M
authors.lastname: Pasqualetti
authors.forename: Kunio
authors.initials: K
authors.lastname: Kitamura
authors.forename: Carlos
authors.initials: C
authors.lastname: Cardoso
authors.forename: Alfonso
authors.initials: A
authors.lastname: Represa
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000235:genetics; D000089662:Doublecortin Protein; D018274:Electroporation; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D059330:GABAergic Neurons / Q000166:cytology / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D018709:Statistics, Nonparametric; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C469264:ARX protein, human; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; C019529:polyalanine; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C013411:biocytin; D008239:Lysine