Abstracts

Rationale: Neonatal seizures are a common problem in neonates resulting in significant short and long-term morbidities. Neonatal seizures are difficult to treat stemming from incomplete understanding of underlying mechanisms as well as lack of reliably effective therapies. The development of neonatal mouse models of hypoxia-induced seizures is critical in the investigation of the molecular mechanisms involved in hypoxic seizures and testing of novel therapies.Methods: EEG data were obtained by stereotaxically implanting 4 monopolar insulated stainless steel electrodes (2 in the ventral hippocampus and 2 in the cortex) in developing (P2 to P12) anesthetized C57BL/6 neonatal mice. Following an overnight recovery period, the mice were exposed to hypoxia (4% for 4 min), a degree and duration of hypoxia for which 75% of P7-P8 animals demonstrate seizures during reoxygenation and mortality is 0%. Pups were monitored via video-EEG throughout the procedure including baseline, hypoxia and reoxygenation. Appropriate placement of hippocampal electrodes was verified anatomically at the end of each experiment.Results: Seizures were observed following reoxygenation in 67% (P3-4), 100% (P5-6), 75% (P7-8) and 80% (P9-10) of pups compared to 20% of P11-12 pups. Mortality was 0% for all age group except for P11-12 pups where a mortality of 60% was observed. Seizure latency was similar in all age groups: 71 17 sec (P3-4); 125 57 sec (P5-6), 98 21 sec (P7-8) and 81 97 sec (P9-10), but was significantly delayed in P11-12 (172 0 sec, p=0.005 vs. P1-2 and P9-10, ANOVA). Seizure duration was similar in all age groups: 23 4 sec (P3-4), 30 4 sec (P5-6), 29 11 sec (P7-8), 43 11 sec (P9-10) and 24 0 sec (P11-12). In addition, hypoxia exposure resulted in significant background suppression in all age groups: 59.7% (P3-4), 56.4% (P5-6), 69.1% (P7-8), 81.3% (P9-10) and 79.3% (P11-12). Following reoxygenation, there was a progressive return to baseline noted in all age group (see figure). Background suppression and EEG recovery was not different among age groups.Conclusions: Developing neonatal mice exposed to brief and severe hypoxia followed by rapid reoxygenation reliably develop seizure during the reoxygenation phase. Future studies are required to investigate long term impact of early life hypoxia-induced seizures in this model.