Anticonvulsants, ischemic seizures and regeneration in the immature brain

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DESCRIPTION (provided by applicant): Neonatal stroke affects one in 4000 term births and frequently results in cognitive impairments. Neonatal strokes present with seizures, and anticonvulsants (usually phenobarbital) are administered for months afterward. Our central hypothesis is that impaired hippocampal neurogenesis after neonatal stroke contributes to cognitive dysfunction, and anticonvulsants modulate both post-stroke neurogenesis and cognitive outcome. More specifically we hypothesize that anticonvulsants increasing GABA signaling decrease hippocampal neurogenesis and impair cognitive outcome, and anticonvulsants inhibiting histone deacetylase increase hippocampal neurogenesis and improve cognitive outcome. Approach: We will use a recently developed immature mouse model of ischemic seizures and brain injury. P12 CD1 mice will receive unilateral carotid ligation and BrdU labeling, and we will measure cognitive function, atrophy, and maturation of newborn hippocampal cells in the same animals. In a separate cohort of animals we will assess post-stroke integration of newborn neurons utilizing Arc-BrdU-NeuN co-labeling after a novel spatial task. We will determine the impact of chronically administered drugs that enhance GABA transmission or inhibit histone deacetylase upon atrophy, neurogenesis, cognitive impairment and chronic seizures in this model. Significance: Stroke in the immature brain causes cognitive impairment that often persists into adulthood. An intervention providing even partial reduction of cognitive impairment would result in significantly improved quality of life and decreased national healthcare costs. This work will determine which anticonvulsant is more likely to improve cognitive outcome after neonatal stroke and conversely which anticonvulsant should be avoided. This work will also reveal mechanistic insights regarding the role of GABA and histone deacetylase in neurogenesis and recovery after neonatal stroke. The background, training, and experience of the PI as a clinician scientist and pediatric neurologist make her uniquely suited and highly motivated to carry out this important research. PUBLIC HEALTH RELEVANCE: Neonatal stroke is an important cause of learning problems that often last into adulthood. Because neonatal stroke presents with seizures, seizure medications are given and usually continued for months afterward. This work will provide important insights as to which seizure medications are more likely to improve new cell birth and learning after neonatal stroke and which should be avoided. The studies will also inform our understanding of processes important to new cell birth and cognitive outcome in the immature brain after neonatal stroke.