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.

Neonatal Estradiol Stimulation Prevents Epilepsy in Arx Model of X-Linked Infantile Spasms Syndrome

“…Although much has been learned about the role of Arx in inter-neuron migration and maturation at critical ages, the large number of transcriptional targets and endophenotype complexity are reminders that our understanding of the epileptogenic role of this pleiotropic transcription factor is only beginning (62, 63). The findings described here identify early disease-modifying effects of gene expression remodeling by transient stimulation with an endogenous steroid hormone and a promising avenue for exploring new treatment options for a devastating infantile epilepsy syndrome.…”

Mechanisms of Epileptogenesis in Pediatric Epileptic Syndromes: Rasmussen Encephalitis, Infantile Spasms, and Febrile Infection-related Epilepsy Syndrome (FIRES)

“…An important common element of the underlying pathology in ARX mice is the loss of GABAergic interneurons from the cortex and, in some cases, hippocampus and striatal regions, which prompted use of the term "interneuronopathy". Interneuronopathy has been found in all ARX mice, with only one exception [76]. Loss of GABAergic interneurons for acquired causes has also been reported in the multiple-hit rat model of IS [80], and is currently one of the investigated "common pathways" for other models of IS.…”

“…ARX is a transcription factor that is involved in ventral telencephalon morphogenesis, migration of GABAergic neuronal progenitors, and early commitment of cholinergic neurons [75]. Seven transgenic mouse models with ARX loss-offunction or knockin mutations have been produced [76][77][78][79]. However, only two of these mouse strains exhibit epileptic spasms, suggesting a heterogeneity in the phenotype, similar to humans, which could be due to either the severity of genetic dysfunction stemming for the gene defect or other modifiers.…”

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

“…Mice with conditional Arx deletion at the dorsal telencephalon (Arx −/Y Emx1 Cre ) do not demonstrate interneuronopathy, consistent with the Emx1 specification for cortical pyramidal neurons (Chan et al 2001; Simonet et al 2014). In contrast, conflicting reports of presence or absence of interneuronopathy have been published for the Arx (GCG)7/Y mice (Beguin et al 2013; Kitamura et al 2009). …”