Abstracts

Rationale: Hypoxic-ischemic encephalopathy (HIE) is the most common initiator of neonatal seizures and a leading cause of long-term disabilities in infants. Survivors are at increased risk of autism, epilepsy, cognitive and learning difficulties and psychiatric conditions. Seizures are thought to compound the initial HIE injury thus, common clinical practice is to suppress neonatal seizures using pharmacotherapies (antiseizure drugs, ASDs) that boost inhibitory transmission (Phenobarbital, PB) or cease excitatory transmission (Levetiracetam, Lev). However, treatment of neonatal seizures poses a particular challenge: both seizures and anti-seizure medications can result in long-term adverse effects on brain development. While there is growing clinical evidence for the adverse impact of both seizures and medication alone, very little is known about how these insults interact. For the first time, we sought to directly compare the effects of the two main ASDs used for neonatal seizure treatment on both naïve animals, and as a therapy for hypoxia-induced seizures, on behavioral outcomes. Understanding complex behavioral outcomes following neonatal seizures with and without ASD treatment is pivotal in identifying novel therapeutics with improved side effects profiles and identifying subtle behavioral consequences of neonatal ASD administration. Methods: Male and female post-natal day 7 (P7) Sprague Dawley pups were subject to graded global hypoxia-induced seizures (Hx) or normoxia (Nx) and treated with vehicle, PB (75 mg/kg) or LEV (200 mg/kg) n=10-12/group/sex. Subsequently at P60, a battery of behavioral and cognitive tests were performed over 20 day period after which the animals were sacrificed. Tests performed included open-field test (OF), elevated plus maze (EPM), looming threat test (LT), novel object recognition (NOL), pre-pulse inhibition (PPI) and passive avoidance test (PA). Results: When ASDs were given to Nx pups, we observed behavioral deficits, more time spent in the periphery (OF), increased freezing and rearing (LT), decreased latency in PA, compared in vehicle. These behavioral changes were not as pronounced when ASDs were given for the treatment of Hx-seizures. However we also observed that Hx animals displayed altered behavior compared to Nx animals. Conclusions: Our results show an effect of sex on behavioral affects later in life following neonatal seizures and ASD treatment, suggesting that although it has been reported that males and females respond differently to HIE (REFS) the response to ASDs is similar. Our results also suggest a divergent effect of PB when given either to normoxic or hypoxic pups. These data suggest that ASD treatment in the neonatal period may act differently in the context of hyperexcitability. Funding: 1R01HD091994-01A1