Abstracts

Rationale: Neonatal seizures are associated with adverse neurodevelopmental outcomes and thus are aggressively treated with anti-seizure medications (ASMs). However, ASM exposure, even in the absence of seizures (e.g., gestational or prenatal exposure), has also been associated with adverse outcomes. However, in the clinical world, it is impossible to separate out the contributions of drug exposure from the underlying pathology or seizure disorder, underscoring the need for animal models. In neonatal rodents, phenobarbital (PHB), induces profound neuronal apoptosis during a constrained period of postnatal development. Another drug, levetiracetam (LEV), avoids this effect. PHB is the first-line therapy for neonatal seizures, while LEV is growing in clinical use for this population. While rodent studies with early-life PHB exposure has shown cognitive impairments later in life, the impact of LEV on cognitive development is unknown. Moreover, prior studies of PHB exposure have focused exclusively on male animals. Due to increasing use of LEV, and the need to assess sex-dependent effects, we sought to test impact of prolonged neonatal ASM exposure on long-term cognitive and social in rat model. Methods: Sprague Dawley rat pups were treated with PHB, LEV, or saline from postnatal day (P)7 to (P)13. Developmental milestones (weight gain, reflex ontogeny) were monitored. Beginning on P45, animals were tested for anxiety-like behavior (open field test, elevated plus maze, light dark test), motor function (locomotor assay, Rotorod test), depression/anhedonia assay (sucrose preference test), social interaction, prepulse inhibition for acoustic startle response, and memory function (novel object recognition task, fear conditioning). Data were analyzed by two-way ANOVA with sex and treatment as between subject factors. Results: PHB, but not LEV, produced a transient but significant impairment in mid-air righting reflex ontogeny in rat pups. This effect was present in both male and female rats. With respect to anxiety-like behavior in the elevated plus maze, we detected a significant sex-by-treatment interaction: female rats treated with PHB displayed decreased anxiety-like behavior later in life. By contrast, in the open field task, male, but not female rats treated with PHB displayed an increase in anxiety-like behavior which was not seen in animals treated with LEV.  No main effect of drug was noted in the Rotarod test for motor function. A significant deficit in prepulse inhibition was found in PHB exposed male, but not female rats, reflective of impaired sensorimotor gating. Finally, PHB exposed rats displayed neophobia but intact memory in the Novel Object Recognition task. Conclusions: The behavioral profile following early-life exposure to PHB is consistent with prior reports. PHB exposed animals show increased anxiety like behavior. LEV, by contrast, displays a more benign profile. In the tests completed thus far, male animals were more severely impacted by PHB exposure than females, raising the possibility of sex-dependent effects. Further examination of the profile of developmental outcomes following common ASMs may help to identify “optimal” therapies while minimizing iatrogenic effects. Funding: MedStar Health Research  Institute New Investigator Associate Grant Fund.