In cases of cardiac arrest or stroke, the brain is deprived of blood, glucose, and oxygen and ischemic damage to specific neuronal populations occurs. One of the major factors that contributes to the ischemic damage is an increased excitability of neurons. Since neuronal excitation can be inhibited by the neurotransmitter, gamma-aminobutyric acid (GABA), the objective of this research plan is to determine the role of GABA neurotransmission in the neuronal damage following transient global ischemia. The model involves occlusion of 4 vessels (cerebral and carotid arteries) in the rat; changes in GABA neurotransmission are determined at both pre and postsynaptic loci. For presynaptic studies, in vivo microdialysis will be used to measure extracellular GABA levels in brain regions selectively vulnerable to ischemic damage. For postsynaptic studies, MRNA expression of GABA/A receptor subunits, GABA/A receptor binding, and function will be assayed using 1) in situ hybridization histochemistry, 2) receptor autoradiography (using [3H]muscimol to label GABA/A agonist sites and [35S]t- butylbicyclophosphorothionate to label the GABA-gated chloride channel, and 3) ion flux techniques to measure GABA gated 36 chloride uptake in synaptoneurosomes from cerebral cortex, hippocampus, and striatum. The research plan is divided into 3 parts to determine: 1) if changes in extracellular GABA levels promote or prevent ischemia-induced neuronal degeneration, 2) if changes in GABA/A receptor expression, binding, and function in selectively vulnerable regions promote or result from ischemia-induced neuronal death, and 3) if pharmacological agents that enhance GABA/A receptor function protect vulnerable neurons from degeneration and preserve GABA/A receptor characteristics and function in rats with transient global ischemia. These studies should provide new insights into the role of GABA neurotransmission in the initiation, promotion, or prevention of ischemic-induced neuronal injury. In addition, these studies may provide the bases for investigating new treatment strategies for dementias and sensorimotor deficits that occur after cardiac arrest and stroke.
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