Low-Dose Perampanel Rescues Cortical Gamma Dysregulation Associated With Parvalbumin Interneuron GluA2 Upregulation in Epileptic Syngap1+/− Mice

Brennan J. Sullivan, Simon Ammanuel, Pavel A. Kipnis, Yoichi Araki, Richard L. Huganir, Shilpa D. Kadam

Research output: Contribution to journalArticle

Abstract

Background: 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. Methods: We established the phenotype of the epileptogenesis in a Syngap1+/− mouse model using 24-hour video electroencephalography (vEEG)/electromyography recordings at advancing ages. We administered an acute low dose of perampanel, a Food and Drug Administration–approved AMPA receptor (AMPAR) antagonist, during a follow-on 24-hour vEEG to investigate the role of AMPARs in Syngap1 haploinsufficiency. Immunohistochemistry was performed to determine the region- and location-specific differences in the expression of the GluA2 AMPAR subunit. Results: A progressive worsening of the epilepsy with emergence of multiple seizure phenotypes, interictal spike frequency, sleep dysfunction, and hyperactivity was identified in Syngap1+/− mice. Interictal spikes emerged predominantly during non–rapid eye movement sleep in 24-hour 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 gamma power modulation during behavioral-state transitions. A significant region-specific increase of GluA2 AMPAR subunit expression in the somas of parvalbumin-positive interneurons was identified. Conclusions: Acute dosing with perampanel significantly rescued behavioral state–dependent cortical gamma homeostasis, identifying a novel mechanism implicating Ca2+-impermeable AMPARs on parvalbumin-positive interneurons underlying circuit dysfunction in SYNGAP1 haploinsufficiency.

Original languageEnglish (US)
JournalBiological psychiatry
DOIs
StateAccepted/In press - Jan 1 2020

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Keywords

  • Gamma oscillations
  • GluA2
  • Intellectual disability
  • Myoclonic seizures
  • Parvalbumin interneurons
  • Perampanel

ASJC Scopus subject areas

  • Biological Psychiatry

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