Glutamate (Glu) is the major fast excitatory neurotransmitter in the mammalian central nervous system (CNS), participating in information processing and the synaptic plasticity that may underlie learning and memory. However, excessive activation of Glu receptors produces neuronal damage and Glu may be involved in the pathophysiology of specific neuropsychiatric disorders. This makes it important to understand factors that regulate Glu-mediated function. Evidence gathered over the past several years indicates that Glu transporters are important regulators of extracellular Glu levels and that glial Glu transporters participate in synaptic transmission. Moreover, glial Glu transport is linked to the nutritive functions of glia, which in turn provide energy support for neurons. In this proposal, experiments are designed to examine the role of Glu transporters in excitatory synaptic function in the hippocampus. The studies will use in vitro hippocampal microisland cell cultures and hippocampal slices to address three specific aims - 1. To examine glial-neuronal interactions in excitatory synaptic transmission and the role of Glu transporters in determining the time course of Glu following release at synapses. These studies will also examine the role of transporters in limiting heterosynaptic interactions resulting from Glu spillover from one synapse onto another. 2. To examine how modulation of Glu transporter function alters synaptic transmission. These studies will examine the shorter- term effects of specific second messenger systems that modulate transporter function and longer-term effects of changes in transporter expression. 3. To understand how changes in glial metabolism influence excitatory synaptic function and synaptic plasticity. These studies will examine conditions under which the release of monocarboxylates from glia participates in synaptic function. It is hoped that these studies will provide useful information about the regulation of Glu-mediated transmission and will lead to insights that help to preserve synaptic function in patients with neuropsychiatric disorders.
