The current proposal focuses on mechanisms and consequences of early-life seizures that are provoked by proconvulsant'stressors' such as fever (hyperthermia) and hypoxia. These non-genetic 'triggered' seizures constitute the majority of developmental seizures. While the outcome of simple febrile seizures is generally benign, and the outcome of many developmental seizures depends on their etiology, emerging evidence in both human and animals indicates that prolonged febrile seizures and recurrent triggered seizures may be associated with neuronal injury. The applicant has demonstrated that the stress-activated neuropeptide, corticotropin releasing hormone (CRH), a well established key mediator of the CNS stress-response, acts as a powerful, age-specific convulsant in the developing brain and promotes injury of hippocampal neurons. Thus, CRH may play a role in the mechanisms by which triggered developmental seizures influence neuronal integrity. During the recent funding period, the applicant established the presence of a significant population of CRH-expressing interneurons in the developing hippocampus and the mechanisms by which CRH interacts with glutamate receptor activation to enhance hippocampal excitability. In addition, recent findings suggest that (1 ) pro-convulsant stressors may increase CRH expression in limbic regions and (2) excessive CRH-receptor activation during early-life may result in significant long-term consequences on hippocampal integrity and function. Therefore, the proposed research tests the hypothesis that proconvulsant stressors increase CRH levels in hippocampus resulting in augmentation by the peptide of excitotoxic mechanisms. to enhance neuronal injury and lead to long-term hippocampal dysfunction. Four experiments are proposed to test this hypothesis: 1 ) studying-using in situ hybridization and immunocytochemistry- whether proconvulsant stressors enhance CRH-expression and levels in hippocampus. Studying the unique mechanisms by which CRH leads to hippocampal neuronal death using (2) in vivo and (3) in vitro dissociated hippocampal cell approaches, and, 4) Examining the significant long-term consequences of excessive CRH-dependent excitation during early life, focusing on hippocampal neuronal loss and hippocampal-dependent cognitive dysfunction. The significance of the proposed studies derives from their focus on mechanisms and consequences of early life provoked seizures that constitute the majority of developmental seizures, but remain relatively unstudied. The proposed studies, delineating age-specific mechanisms for seizure-related neuronal injury and its consequences should lead to the development of novel, age-appropriate, specific therapies to prevent these consequences.
Showing the most recent 10 out of 109 publications
