Activity of Glutamate Transporter GLT1 in CA3 Neurons

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DESCRIPTION (provided by applicant): Glutamate transporters in the brain play at least two critical roles at excitatory synapses: maintenance of low extracellular glutamate levels, which supports normal activation of glutamate receptors and prevents excitotoxic degeneration of neurons, and modulation of the concentration time course of glutamate in the extracellular space. Five glutamate transporter isoforms have been identified, of which GLT-1 (termed EAAT2 in human) accounts for up to 95% of total glutamate transport activity. In the normal CNS, GLT-1 protein is largely restricted to astrocytes where it plays a dominant role in clearing extrasynaptic glutamate. Evidence for neuronal expression of GLT-1 mRNA, as well as biochemical and electrophysiological data suggesting the presence of pre-synaptic transporters, has been reported, but there has been no strong evidence of functional GLT-1 protein in neurons. To examine the biology of cell-specific transporter regulation, I generated GLT1-BAC-promoter transgenic mice. Using these animals, we have now identified GLT-1 promoter activity, and, subsequently, glutamate transporter currents, selectively in mouse hippocampal CAS neurons. The goals of this proposal are to establish the identity and subcellular location of the GLT-1 transporter in CAS neurons, to investigate regulation of its expression, and to assess its potential role in synaptic transmission. These experiments will begin to directly test the functional significance of GLT-1 in neurons.