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

Epileptic encephalopathies comprise a heterogeneous group of severe infantile disorders for which the pathophysiological basis of epilepsy is inaccurately clarified by genotype-phenotype analyses. Because a deficit of GABA-neurons has been found in some of these syndromes, notably in patients with X-linked Lissencephaly with Abnormal Genitalia (XLAG), 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 is unaltered in these mice. Interestingly, electrophysiological recordings show that hippocampal pyramidal neurons displayed a frequency of inhibitory postsynaptic currents similar to wild-type mice. However, these neurons show a dramatic increase in the frequency of excitatory inputs associated to a remodeling of their axonal arborization, suggesting that epilepsy in Arx(GCG)7/Ymice 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.