The amino acid transmitter GABA exerts a dual action across the life span. Acting via the GABA-A receptor, GABA is a major source of neuronal excitation in immature and developing neurons. But in mature neurons, GABA is the predominant mediator of synaptic inhibition. Divergence in GABA action in the male versus female brain during neonatal development has recently been identified as a critical junction in sexual differentiation. The current proposal extends these findings to include a role for GABA in prenatal brain damage, increasing the risk of disabilities associated with cognition and affect. Males suffer worse outcomes following neonatal brain damage, and hormonal modulation of GABA action may be a contributing variable to this increased susceptibility. Preterm human infants are at high risk for brain injury resulting from trauma related to pregnancy or birth (e.g. pre-eclampsia, strangulation by the umbilical cord) or neurotrauma within the fetus itself (e.g. stroke, seizures). Often following these events there is an increase in extracellular levels of GABA. This proposal investigates the novel hypothesis that exogenous muscimol, a selective GABA-A receptor agonist, induces damage in the newborn rat hippocampus, and may serve as a model of preterm human infant brain damage. In immature neurons, opening GABA-A receptors causes chloride efflux, resulting in membrane depolarization and opening of calcium channels, thereby increasing intracellular calcium. While the effect of GABA receptor activation and endogenous calcium influx during development are generally considered to be trophic, excessive calcium influx is an integral component of brain injury. The current proposal focuses on characterizing the effect of estradiol pretreatment on calcium influx following GABA receptor activation in Specific Aim 1, determining the effect of estradiol and muscimol on the developmental change in the reversal potential for chloride in Specific Aim 2, documenting the effect of an estradiol isomer that binds with low affinity to the estrogen receptor on muscimol-induced hippocampal damage in Specific Aim 3, and investigating alternative models of preterm infant brain injury in the baboon and rat in Specific Aim 4. My long-term career goals are to become an independent scientist at a major research-oriented academic institution, and to make important contributions to the field of pediatric neurology. I intend to pursue this research in a laboratory of my own.
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