Blockade of glutamate transporters facilitates cerebellar synaptic long-term depression.

Excitatory amino acid transporters (EAATs) are believed to limit extracellular glutamate concentrations with specific roles poorly understood. At cerebellar climbing fiber-Purkinje cell synapse, EAAT4 and metabotropic glutamate receptor 1 (mGluR1) are closely expressed in surrounding postsynaptic locations, suggesting that EAAT4 may regulate mGluR1 activation. We examined the actions of EAAT4 on synaptic plasticity by applying blockers of glutamate transporters, DL-threo-beta-benzyloxyaspartic acid and D-aspartate. Inhibition of EAAT4 markedly prolonged AMPA receptor-mediated excitatory postsynaptic currents evoked by stimulating climbing fibers. Impairing glutamate uptake facilitated mGluR1-dependent climbing fiber-Purkinje cell synaptic long-term depression (LTD). Glutamate uptake blockers also sufficiently rescued climbing fiber-Purkinje cell synaptic LTD that failed to be induced by a weaker tetanus. Our results suggest that neuronal glutamate transporters strongly influence mGluR1-dependent cerebellar LTD.