Abstracts

Rationale: Hypoxic-ischemic encephalopathy (HIE)-associated seizures respond poorly to 1st line AEDs and therefore pose a serious challenge for acute clinical management. The etiology and severity of neonatal seizures are known to dictate long-term outcomes; however, the long-term neurologic consequences of neonatal seizures in pre-clinical models are not extensively evaluated. Using a CD1 mouse model of neonatal ischemia, with documented age-dependent seizure susceptibility, stroke injury and PB-resistance, this study aimed to ascertain the long-term effects of neonatal ischemic seizures at postnatal day 7 vs. 10 (P7 vs. P10).Methods: This study evaluated the long-term behavioral phenotypes and 24h EEG in adult mice with or without history of neonatal ischemic seizures at P7 vs. P10. Acute seizures were induced by unilateral permanent ligation of right common carotid, and the seizure burdens were quantitated using video-electroencephalogram (EEG) for 3h after ligation. Behavioral tests (Y mazes, elevated plus maze, open field, and prepulse inhibition [PPI]) were conducted at ages P80 and P130. At P120, twenty-four hour quantitative video/EEG/EMG was recorded and evaluated for activity states, sleep structure and spectral analyses.Results: The acute neonatal seizure susceptibility and severity in this study replicated the age-dependent characteristics at P7 and P10 previously established for the model. Open-field tests at P80 and P130 revealed that habituation for both P7 and P10 groups were impaired but differentially. The P10 group showed an earlier onset of impaired habituation at P80 while the P7 group did not. A subset of ligated-mice (P10 >P7) displayed hyperactivity (~400%) in open-field test and confirmed on 24h EMG done at P120. PPI sensitivity was absent in both P7 and P10 groups at P80. Neither P7 nor P10 groups significantly differed in their performances in Y-mazes and elevated plus-maze compared to controls. Twenty-four hour qEEG recordings at P120 revealed significantly altered sleep/wake cycles in P10 but not in P7 ligated-mice. The ligated-groups (both P7 and P10) had lower weights as adults and in males this was significantly lower compared to age-matched controls.Conclusions: Long-term neurological comorbidities following neonatal ischemic seizures were differential by age of neonatal ischemia (P7 vs. P10) and also evolved with advancing age from P80 to P130.