RRC ID 17568
Author Beguin S, Crépel V, Aniksztejn L, Becq H, Pelosi B, Pallesi-Pocachard E, Bouamrane L, Pasqualetti M, Kitamura K, Cardoso C, Represa A.
Title An epilepsy-related ARX polyalanine expansion modifies glutamatergic neurons excitability and morphology without affecting GABAergic neurons development.
Journal Cereb Cortex
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.
Volume 23(6)
Pages 1484-94
Published 2013-6-1
DOI 10.1093/cercor/bhs138
PII bhs138
PMID 22628459
MeSH 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology Action Potentials / drug effects Action Potentials / genetics Age Factors Animals Animals, Newborn Cell Movement / genetics Doublecortin Protein 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*
IF 5.043
Times Cited 26
Mice RBRC03654