Parvalbumin interneurons and dentate gyrus homeostatic dysregulation shape epileptogenesis in Angelman syndrome model mice

The process of transitioning from seizure-resistant to seizure-prone is crucial for the development of better epilepsy treatments. To explore this, researchers examined Angelman syndrome (AS) mice models, which naturally exhibit heightened susceptibility to seizure kindling due to the absence of the maternal Ube3a (mUbe3a) allele.

The study identified parvalbumin-expressing (PV+) interneurons as crucial regulators of this process. When mUbe3a was selectively deleted in these PV+ neurons, it replicated the increased AS epileptogenesis observed in the mice. Conversely, restoring UBE3A broadly in GABAergic neurons increased seizure resistance. Additionally, pathological changes in the extracellular matrix of the dentate gyrus corresponded to increased susceptibility to post-kindling seizures, underscoring the region's significance in enhanced epileptogenesis.

The researchers discovered a "two-hit" electrophysiological phenomenon in AS model mice: kindling did not recruit counterbalancing inhibition onto dentate granule cells but rather promoted their maladaptive intrinsic hyperexcitability. In summary, these findings establish a connection between cell type-specific inhibitory dysfunction and altered homeostatic plasticity, as key drivers of epileptogenesis. This suggests potential avenues for circuit-focused treatment approaches in the future.