GLUTAMATE TRANSPORTER FUNCTION AT EXCITATORY SYNAPSES
Embargo until
Date
2006-08-03T15:29:15Z
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
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.