Anticonvulsants, ischemic seizures and regeneration in the immature brain

Hugo W. Moser Res Inst Kennedy Krieger, Baltimore MD

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Abstract

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.