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

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 1/2 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 1/2 mice. Interictal spikes emerged predominantly during non-rapid eye movement sleep in 24-hour vEEG of Syngap1 1/2 mice. Myoclonic seizures occurred at behavioral-state transitions both in Syngap1 1/2 mice and during an overnight EEG from a child with SYNGAP1 haploinsufficiency. In Syngap1 1/2 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 Ca 21-impermeable AMPARs on parvalbumin-positive interneurons underlying circuit dysfunction in SYNGAP1 haploinsufficiency.

SynGAP is expressed in the murine suprachiasmatic nucleus and regulates circadian‐gated locomotor activity and light‐entrainment capacity

“…Of note, while our manuscript was under review, locomotor video tracking data from Sullivan et al. (2020) reported a similar increase in nigh time motor activity in Syngap1 +/− mice compared to WT animals. Interestingly, our studies show that this same hyperactive phenotype was also observed in LL conditions—wherein Syngap1 +/− mice displayed increased overall activity relative to their WT littermates.…”

GABAergic signaling promotes early-life seizures in epileptic SYNGAP1+/-mice

“…Additionally, the detrimental effects of prolonged sleep deprivation on cognitive performance are also well established [37][38][39][40] . Our previous study established significant disruption of cortical gamma homeostasis in adult Het +/mice 15 . The identification of normal slow wave sleep compensation to the increased sleep pressure in both WT +/+ and Het +/pups highlight the uniqueness of the qEEG biomarker related to gamma homeostasis which is known to depend on function of fast-spiking PV interneurons 41,42 .…”

“…All surgical procedures and perampanel (PMP) dosing implemented in this study were as previously published 15 . At P18 subdural EEG and suprascapular EMG electrode implantation was performed under isoflurane anesthesia (4%–1.5%).…”

“…Heterozygous SynGAP mice (Het +/-) present with impaired learning and memory, sensory processing, hyperactivity, sociability, and epilepsy in adulthood [12][13][14][15][16][17][18][19] . During development, Het +/pups demonstrate precocious unsilencing of thalamocortical synapses, abnormal dendritic spine dynamics, accelerated neuronal maturation, and reduced experiencedependent plasticity 13,20,21 .…”

“…Previously, we have characterized the natural progression of the epilepsy and seizure phenotypes at advancing adult ages in Het +/- mice 15 . This was associated with a significant impairment in cortical gamma (35-50Hz) and a significant increase in parvalbumin (PV) interneuron GluA2 expression.…”