EAAT3 Contribution to Glutamate Uptake in the Hippocampus

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DESCRIPTION (provided by applicant): Removal of the excitatory neurotransmitter glutamate from the synaptic cleft and extracellular space is critical in preventing excitotoxicity and neuronal cell death. Glutamate is cleared by excitatory amino acid transporters (EAATs). These EAATs are expressed on both neurons and glial cells in the central nervous system, and they work by harnessing the electrochemical energy of ions to drive glutamate translocation into the cell. Glial cell EAAT function is known to be crucial for glutamate clearance in the brain; however, the role of neuronal EAATs in specific brain areas, such as the hippocampus, has not been clearly defined. CA1 pyramidal neurons express low levels of a neuron specific subtype, EAATS; nonetheless conventional electrophysiological methods have been unable to detect EAATS functionality. The long-term goal of this application is to dissect the role of neuronal EAATS in the hippocampus and elucidate its effect on synaptic transmission. By using a highly sensitive electrophysiological approach, this project will attempt to detect EAATS functionality in hippocampal neurons. The aims of this proposal are 1) to determine transporter density differences between subpopulations of hippocampal neurons and 2) to examine the effects of EAATS on synaptic transmission in the hippocampus. Glutamate, the most abundant excitatory neurotransmitter in the brain, stimulates communication between neurons and plays a crucial role in brain function; however, in excess, glutamate can have neurotoxic effects resulting in neuronal cell death. To avoid this problem, neurons and glia, neuronal support cells, employ glutamate transport molecules, which actively transport the glutamate molecules into the cells and prevent neurotoxicity. The majority of research to date has focused on glutamate transporter subtypes expressed on glial cells, but little is known about the specific function of neuronal transporters, in particular, those expressed on neurons in the hippocampus. Deciphering the role played by neuronal glutamate transporters in the hippocampus will provide useful insight into normal brain function and prevention of excess glutamate neurotoxicity.