Abstracts

Rationale: The prolonged seizures of status epilepticus (SE) occur due to the failure of seizure termination mechanisms or the initiation of changes that could sustain seizures for longer periods. Febrile SE accounts for 25-30% of pediatric SE episodes. The mechanisms that could sustain these seizures for prolonged periods in a developing brain are unclear. Glutamatergic transmission of hippocampal neurons is potentiated in adult animals in SE, whether it is also potentiated during pediatric SE remains unexplored. We evaluated the plasticity of AMPA receptors (AMPARs) during hyperthermia-induced SE. GluA1 are the most abundantly-expressed AMPAR subunits in the hippocampi of P10 and older animals. Hence, we evaluated whether deleting the GluA1 subunit expression could alter susceptibility to hyperthermia-induced SE (hSE).

Methods: hSE was induced in 16- or 17-day-old (P16/17) wild type C57Bl6 or littermate mice with a global deletion of GluA1 subunits (GluA1 KO) of either sex. Bilateral cortical and hippocampal electrodes were implanted to record seizures using continuous video EEG. To induce the seizure, the pups were placed in a hyperthermia chamber with seizure commencing when core and brain temperature reached approximately 43°C. Once the seizure started, the animals were maintained at 34°C until the seizures ended and the EEG activity returned to baseline. The AMPAR-mediated synaptic currents were recorded from hippocampal CA1 neurons of C57Bl6 animals in hSE and normothermia littermate controls using standard voltage-clamp techniques.

Results: The AMPAR synaptic currents of CA1 neurons were potentiated in hSE animals. The AMPAR-mediated sEPSCs recorded from animals in hSE were of larger amplitude (hSE: 26±1 pA, n=6 neurons/3 animals vs controls: 22±1 pA, n=6 neurons/3 animals, p=0.049, students t-test); other properties of sEPSCs were similar in hSE and control animals. Next, we evaluated whether the hSE was altered in GluA1KO mice. Spike-wave discharges with amplitude at least twice that at the baseline and frequency higher than 2 Hz marked the onset of seizures following hyperthermia exposure. The occurrence of these discharges for 5 min or longer marked the onset of hSE. All the WT mice (n=5) experienced hSE. In contrast, only one of the 5 GluA1KO mice experienced hSE (p=0.048 Fisher’s exact test). The seizures lasted for 28±10 min (n=5) in the WT mice. The seizure duration was 9 min in the one GluA1KO mouse that experienced SE.

Conclusions: These studies revealed the potentiation of AMPAR-mediated glutamatergic transmission of hippocampal CA1 neurons of animals in hSE. Mice lacking the GluA1 subunit expression were resistant to induction of hSE. Thus, potentiation of AMPAR-mediated glutamatergic transmission is a factor underlying the prolonged seizures of SE in young animals. Additional studies evaluating the effect of hyperthermia on the plasticity of AMPAR-mediated neurotransmission and surface membrane trafficking of these receptors could provide additional insights into the mechanisms regulating the SE-associated plasticity of these receptors.

Funding: SJ is supported by NINDS grant NS110863.