Consequences of over-activation of the GABAA receptor, such as following consumption of alcohol , seizures and exposure to anesthesia

GABA is the predominant inhibitory neurotransmitter in the central nervous system in the adult, with activation of the GABAA receptor resulting in chloride influx and membrane hyperpolarization. This is in stark contrast to the effect of GABAA receptor activation in the late embryonic/early postnatal brain. During this time period, GABAA receptor activation leads to chloride efflux and membrane depolarization sufficient to open voltage sensitive calcium channels. Excessive calcium influx via this mechanism results in cell death and altered anatomy and behavioral/cognitive abilities. The goal of this research proposal is to investigate the mechanism of GABAA receptor mediated calcium influx as a mitigator of early brain injury and characterize the interaction between the developing GABAergic system, calcium influx and the steroid hormone estradiol. This goal has been undertaken by pursuing four Specific Aims: 1) characterize the effect of 17ß-estradiol pretreatment on calcium transients following GABAA receptor activation, 2) determine the effect of muscimol, the selective GABAA receptor agonist, and 17ß-estradiol on the developmental change in the reversal potential for chloride, 3) document the effect of the biological isomer of 17ß-estradiol, 17a-estradiol, on muscimol-induced hippocampal damage, and 4) investigate alternative models of preterm brain injury in the baboon and rat.