Fluoxetine recovery of synaptic dysfunction following juvenile global cerebral ischemia

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ABSTRACT Global cerebral ischemia caused by cardiac arrest results in many neurological sequelae, including deficits in learning and memory. These deficits are as evident in children as they are in adults, though some report that there is improved recovery in the developing brain over time. The resulting neurological sequelae from pediatric cardiac arrest likely arise from both neuronal death and altered physiology in surviving neurons. Surprisingly, while we know a great deal about ischemic consequences in adults, very little is known about the juvenile brain in response to global ischemic insults, thus leading to very few, if any, therapies for children after cardiac arrest. Therefore, we have developed a novel mouse model of juvenile cardiac arrest that mimics very early childhood to address these questions. Our preliminary data suggests that functional impairment in learning and memory occurs in the juvenile brain, followed by recovery at chronic time points. While this recovery is important, we contend that there is a large amount of time in which intervention can occur to maximize the learning potential of children in school age years. A large part of research focuses on discovery of therapeutics to enhance functional recovery. Hence, we have designed an intervention timeline that has the potential to dramatically alter current therapeutic windows. For adults and neonates who suffer global ischemia, the standard of care remains therapeutic hypothermia, or cooling of the head and/or body to limit neuronal injury when started within hours of ischemia. This same strategy does not protect the childhood brain. Additionally, no pharmacologic agents to protect neuronal injury after ischemia have been translated for use in people. Therefore, we have taken a novel approach to improving and restoring function after global cerebral ischemia. This grant application tests the hypothesis that the neurons that survive ischemia have impaired function, and this impairment can be targeted for intervention. Our preliminary data suggests that administration of fluoxetine 7-14 days after ischemic insult can reverse functional impairments. Specifically, there is evidence that fluoxetine increases brain-derived neurotropic factor (BDNF), a molecule that is vital to mechanisms of learning and memory, as well as the BDNF receptor tyrosine kinase B (TrkB), to rescue impaired synaptic plasticity after global cerebral ischemia. We propose experiments using electrophysiology, behavior, pharmacology, genetic manipulation and intracellular signaling interrogation to address the hypothesis: Delayed administration of fluoxetine activates BDNF-TrkB signaling to restore impaired synaptic function and cognitive following juvenile global cerebral ischemia. If the preliminary data presented in this application suggesting delayed administration of fluoxetine reverses functional impairments are supported, then we may be upon a paradigm shifting strategy and high translational potential through extending therapeutic windows after global cerebral ischemia in children through novel neurorestorative strategies, which perhaps, could be extended to adults and neonates as well.