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

ObjectiveSYNGAP1 encephalopathy is a developmental and epileptic encephalopathy caused by pathogenic loss of function variants. Syngap1-heterozygous (Het+/-) mice demonstrate progressive epilepsy with multiple seizure phenotypes in adulthood. Here, we investigate early-life seizures in Het+/- pups and explore of Syngap1 encephalopathy during development. MethodsPost-natal day 7 (P7) and P12 mice were investigated by tethered video-electroencephalographic (vEEG). The effects of GABAergic drugs phenobarbital (PB) and pentylenetetrazol (PTZ) were investigated at P7 and P12, respectively. 24h tethered vEEG was performed at P24, and telemetric 24h vEEG with 6h sleep deprivation was performed at P35. The effect of perampanel (PMP), an AMPA receptor antagonist, was investigated at P24. ResultsHet+/- mice have spontaneous early-life seizures that lack an overt behavioral phenotype. These subclinical seizures are refractory to PB, but the GABAA receptor (GABAAR) antagonist PTZ significantly reduced seizure frequency suggesting that GABAergic signaling may promote seizure generation in Het+/- pups. At juvenile ages, Het+/- pups recapitulated the early emergence of high gamma (35-50Hz) during NREM and disruption of behavioral-state gamma homeostasis. This biomarker was significantly exacerbated in Het+/- pups after increasing sleep pressure with sleep deprivation. SignificanceSeizures during development have adverse effects on cognitive function. Therefore, an improved understanding of the SYNGAP1 epilepsy during developmental ages is necessary to delineate the deleterious interactions between aberrant synaptic function and recurrent seizures. The development of evidence-based therapies for early-life intervention will benefit from these insights.