Extremely premature birth poses a substantial risk for long-term developmental and cognitive impairment, even in the absence of overt brain injury. We hypothesize that the neonatal brain is unusually sensitive to sub-lethal hypoxic and ischemic injury because of the level of synaptic remodeling that occurs during this period. However, the factors that underline synaptic plasticity are poorly understood and almost impossible to study in neonatal children. Based on a now substantial body of evidence it has become clear that the neuronal spectrin cytoskeleton contributes to synaptic organization, shape, and responsiveness. Closely associated with this role appears to be its sensitivity to Ca++ activated neutral proteases like mu-calpain. In order to study the in vivo role of calpain cleavage of spectrin on processes involved with brain development, and its response to injury, transgenic mice will be prepared that express human brain spectrin that has been mutated so as to reduce its susceptibility to calpain cleavage. These mice will be analyzed for evidence of impaired brain maturation, electrophysiologic function, synaptic density and other changes. The responses of these mice to sub lethal hypoxic and ischemic stress will also be evaluated. Collectively, these studies promise to yield our first real insights into the role of the spectrin skeleton in synapse ecology, and may provide a unique in vivo model for examining the consequences of perinatal brain damage.
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