Short and long-term impact of neonatal seizures on hippocampal granule cell integ

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DESCRIPTION (provided by applicant): The hippocampus is a structure located deep in the brain that is critical for memory, language development, cognition and even imagination. Surprisingly, this is one of the few regions of the adult brain where new brain cells are generated. These new cells are important for the proper functioning of the hippocampus. Unfortunately, recent studies demonstrate that these new cells are vulnerable to seizures. Seizure activity in the brain can cause these immature cells to form the wrong connections with other brain cells. In adults, these abnormal cells likely lead to cognitive problems and perhaps even the development of epilepsy. Distressingly, in children, the situation may be even worse. First, children exhibit a much lower seizure threshold than adults. Seizures in children, therefore, are common. Second, the developmental period during which children exhibit higher seizure incidence overlaps with the peak period of hippocampal development. Large numbers of hippocampal cells are generated in infants, and these cells undergo extensive development through early childhood. Seizures during this period could lead to the abnormal wiring of large numbers of hippocampal cells. In contrast, the generation of neurons in almost all other brain regions is largely complete by birth. To determine whether new hippocampal cells are uniquely vulnerable to insult, and whether disruption of these cells might account for the severe cognitive deficits experienced by children who have intense or recurrent seizures, we utilize a mouse model system in which newly generated hippocampal cells are labeled with green fluorescent protein (GFP). GFP reveals the complete structure of these cells, and by selectively labeling newly generated cells, the population hypothesized to be must vulnerable can be tracked as the animals develop to assess how they connect with other brain cells. The development of immature cells exposed to neonatal seizures will be compared to cells from normal animals using confocal microscopy. These studies will provide important insights into the long-term consequences of neonatal seizures, will inform clinicians about how aggressively to treat children having seizures with anticonvulsant drugs and will help to establish whether disrupted hippocampal cell integration might account for the negative consequences of neonatal seizures. PUBLIC HEALTH RELEVANCE: Seizures in children are common. The long term consequences of these seizures, however, are still unclear. Here, we will examine the impact of neonatal seizures on the development of a brain region critical for learning, language development, cognition and imagination. These studies will help to determine whether and how neonatal seizures harm young brains, and will guide the development of mitigating strategies and treatments.