Low-dose Perampanel rescues cortical gamma dysregulation associated with parvalbumin interneuron GluA2 upregulation in epileptic Syngap1^+/- mice

Loss-of-function SYNGAP1 mutations cause a neurodevelopmental disorder characterized by intellectual disability and epilepsy. SYNGAP1 is a Ras-GTPase-activating protein that underlies the formation and experience-dependent regulation of postsynaptic densities. The mechanisms that contribute to this proposed monogenic cause of intellectual disability and epilepsy remain unresolved. Here, we establish the phenotype of the epileptogenesis in a Syngap1^+/- mouse model using 24h video electroencephalogram/electromyogram (vEEG/EMG) recordings at advancing ages. A progressive worsening of clinically-similar seizure phenotypes, interictal spike frequency, sleep dysfunction, and hyperactivity was identified in Syngap1^+/- mice. Interictal spikes emerged predominantly during NREM in 24h vEEG of Syngap1^+/- mice. Myoclonic seizures occurred at behavioral-state transitions both in Syngap1^+/- mice and during an overnight EEG from a child with SYNGAP1 haploinsufficiency. In Syngap1^+/- mice, EEG spectral power analyses identified a significant loss of cortical gamma homeostasis during behavioral-state transitions from NREM to Wake and NREM to REM. The loss of gamma homeostasis was associated with a region- and location-specific significant increase of GluA2 AMPA receptor subunit expression in the somas of parvalbumin-positive (PV+) interneurons. Acute dosing with Perampanel, an FDA approved AMPA antagonist significantly rescued cortical gamma homeostasis, identifying a novel mechanism implicating Ca²⁺ impermeable AMPARs on PV+ interneurons underlying circuit dysfunction in SYNGAP1 haploinsufficiency.