Paper details

Epilepsy is characterized by recurrent seizures due to neuronal hyperactivity. Approximately 75% of epilepsy begins during childhood. ARX is implicated in a wide spectrum of X-linked neurological disorders. Poly-alanine repeat mutations in ARX have been found in patients with mental retardation and epilepsy with no apparent brain developmental abnormalities. Animal models have shown that Arx is critical for cortical interneuron development and migration. In addition, Arx polyalanine expansion (PAE) modifies glutamatergic neurons excitability and morphology.

Precision models of ARX-associated genetic epilepsies

To elucidate the impact of PAE in ARX gene in human, we have generated “epilepsy-in-a-dish” models from human induced pluripotent stem cells (iPSCs) using cortical and subpallium spheroids (hCS and hSS, respectively). We first detected ARX expression during spheroid differentiation. Then, we generated hCS and hSS from ARX mutated patient and healthy control iPSCs.

When we analyzed hCS at different time points, we found a significant increase of progenitor cells and deep cortical neurons at 30 DIV but a decrease of upper layer neurons. In contrast, upper layer neurons were increased at 120 DIV. Moreover, ARX hSS showed interneurons migration defects. These data suggest that ARX affects cell proliferation and neuronal differentiation during human cortical development.