Nanostring mRNA expression profiling of P7 Arx(GCG)10+7 neonatal cortex using nCounter® mouse Neuropathology Plus Panel

X-linked infantile spasms syndrome (ISSX) is a clinically devastating
developmental epileptic encephalopathy with life-long impact.
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. Neonatal
presymptomatic treatment with 17β-estradiol (E2) in Arx(GCG)10+7 reduces
spasms and modifies progression of epilepsy. 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. 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. NeuN+ (also
known as Rbfox3) survival was also not impacted, suggesting a vulnerable
subpopulation in the immature Arx(GCG)10+7 cortex. Inflammatory processes
during this period might explain this transient elevation in apoptosis;
however, transcriptomic and immunohistochemical profiling of several
markers of inflammation revealed no innate immune activation in
Arx(GCG)10+7 cortex. Neither neonatal E2 hormone therapy, nor ACTH(1-24),
the frontline clinical therapy for ISSX, diminished the augmented
apoptosis in Arx(GCG)10+7, but both rescued neocortical Arx+ cell density.
Since early E2 treatment effectively prevents seizures in this model,
enhanced apoptosis does not solely account for the seizure phenotype, but
may contribute to other aberrant brain function in ISSX. However, since
both hormone therapies, E2 and ACTH(1-24), elevate the density of cortical
Arx+-interneurons, their early therapeutic role in other neurological
disorders hallmarked by interneuronopathy should be explored.