Mental retardation can occur as a result of perinatal brain injury in both the term and preterm neonate. The overall goal of this research program is to elucidate age-specific mechanisms of hypoxic/ischemic perinatal brain injury and to devise age-specific therapeutic strategies for this injury. The specific focus of the laboratory is on two common sequelae of hypoxia/ischemia in the newborn, neonatal seizures and periventricular leukomalacia (PVL). The highest incidence of seizures during life occurs in the neonatal period, and one of the most common causes of seizures in this period is hypoxic/ischemic encephalopathy. Seizures associated with hypoxia are often refractory to therapy and can be associated with long term epilepsy. A research goal is to determine the age-specific mechanisms of such seizures that might contribute to their relative resistance to conventional antiepileptic drugs that are effective at older ages and also to determine the effect of these seizures on subsequent brain development and epileptogenesis later in life. The second major focus of the laboratory is on age-specific mechanisms of white matter injury in the developing brain. PVL occurs in preterm infants, is thought to be a result of cerebral hypoxia/ischemia, and is the most common pathology associated with the subsequent diagnosis of cerebral palsy in premature infants. Research goals associated with this project evaluate age-specific mechanisms of OL injury in vitro and in vivo and extend these studies to pharmacologic protective trials in vivo.