GLUTAMATE TRANSPORTER FUNCTION AT EXCITATORY SYNAPSES
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Glutamate uptake by high-affinity plasma membrane transporters is essential for maintaining a low ambient level of glutamate and avoiding neurotoxicity. At excitatory synapses, glutamate transporters help to terminate glutamate transients following release, restrict diffusion of glutamate between synapses, recycle glutamate for subsequent release, as well as provide glutamate for metabolic purposes. Five different glutamate transporters have been identified in the mammalian central nervous system (CNS); GLAST (EAAT1) and GLT-1 (EAAT2) are found predominantly in glial cells, and EAAC1 (EAAT3) and EAAT4 are expressed by neurons. Despite our knowledge about the localization and density of these transporters, their relative contribution to uptake of synaptic glutamate and their differential impact on transmission are poorly understood. This is mainly because antagonists selective for each type of glutamate transporter have not yet been developed. In this study, we performed electrophysiological recordings in wild-type and genetically modified mice defective in selective glutamate transporters to address the following questions: (1) What are the relative contributions of neuronal and glial glutamate transporters to glutamate uptake at excitatory synapses and (2) how do different types of glutamate transporters influence transmission at excitatory synapses? We examined synaptic clearance of glutamate at two representative excitatory synapses in the rodent brain: climbing fiber-Purkinje neuron synapses in the cerebellum, where neuronal glutamate uptake can be directly measured; and oriens-lacunosum moleculare interneuron synapses in the hippocampus, where iii glutamate clearance at perisynaptic locations can be monitored. We found that at climbing fiber-Purkinje neuron synapses, neuronal transporter EAAT4 but not EAAC1 contributes to the clearance of glutamate, and astroglial transporters remove the majority of synaptic glutamate; at the hippocampal interneuron synapse, astroglial but not neuronal transporters regulate the occupancy of perisynaptic metabotropic glutamate receptors during transmission. We also observed that GLT-1, the predominant astroglial glutamate transporter, is expressed by a selective population of neurons, the hippocampal CA3 pyramidal neurons. The potential function of GLT-1 in these neurons is discussed.