[Role of glutamate transporters in excitatory synapses in cerebellar Purkinje cells].

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Ozawa S

[Role of glutamate transporters in excitatory synapses in cerebellar Purkinje cells].

Brain Nerve. 2007 Jul;59(7):669-76.

PubMed ID

17663137 [ View in PubMed

]

Abstract

Glutamate transporters play critical roles in the maintenance of low extracellular concentrations of glutamate, which protects neurons from excitotoxic injury. The activity of these transporters also restricts the amplitude and duration of excitatory postsynaptic currents (EPSCs) in glutamatergic synapses. In the CNS, five distinct glutamate transporters (GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3, EAAT4 and EAAT5) have been cloned. Glial glutamate transporters, GLAST and GLT-1, are expressed on surface membranes of processes of Bergmann glia (BG) wrapping excitatory synapses on dendritic spines of Purkinje cells (PCs) in the cerebellum. GLAST is a dominant glutamate transporter in BG, being expressed 6-fold more abundantly than GLT-1. To clarify roles of the transporters in BG, we analyzed the properties of climbing fiber- and parallel fiber-mediated EPSCs (CF-EPSCs and PF-EPSCs) in PCs of GLAST-deficient mice. We also used a novel antagonist of glutamate transporters, (2S,3S)-3-[3-(4-methoxybenzoylamino) benzyloxy] aspartate (PMB-TBOA) that specifically blocks GLAST and GLT-1 at extremely low concentrations. In the GLAST-deficient mice, the application of cyclothiazide (CTZ) that reduces desensitization of AMPA receptors increased the peak amplitude of the EPSCs and prolonged their decays more markedly than in wild-type mice, indicating that GLAST contributes to the uptake of glutamate that floods out of the synaptic cleft. Furthermore, multiple discrete steps of CF-EPSCs composed of a conventional fast-rising CF-EPSC and small, slow-rising EPSCs occurred in 80% of PCs tested in GLAST-deficient mice. These multiple discrete steps of CF-EPSCs were also induced in wild-type mice by the application of PMB-TBOA. This indicates that the glial transporters in BG prevent glutamate released from a single CF from spilling over to neighboring PCs other than the synaptically connected PC, and thus play an essential role in the maintenance of the functional one-to-one relationship between CFs and PCs. Differential roles of the glial and neuronal glutamate transporters in PC synapses are also discussed.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Aspartic acid	Excitatory amino acid transporter 3	Protein	Humans	Unknown	Not Available	Details