In the first postnatal week, we identified a transient wave of elevated apoptosis in Arx (GCG)10+7 mouse cortex that is non-Arx cell autonomous, since mutant Arx-immunoreactive (Arx +) cells are not preferentially impacted by cell death. Cortical pathology during this period, a crucial point for clinical intervention in ISSX, has largely been unexplored, and the pathogenic cellular defects that are targeted by early interventions are unknown. Neonatal presymptomatic treatment with 17β-estradiol (E2) in Arx (GCG)10+7 reduces spasms and modifies progression of epilepsy. Arx (GCG)10+7, a mouse model of the most common triplet-repeat expansion mutation of ARX, exhibits neonatal spasms, electrographic phenotypes and abnormal migration of GABAergic interneuron subtypes. X-linked infantile spasms syndrome (ISSX) is a clinically devastating developmental epileptic encephalopathy with life-long impact.
