Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression

Neuronal and glial isoforms of glutamate transporters show distinct distrib utions on membranes surrounding excitatory synapses, but specific roles for transporter subtypes remain unidentified. At parallel fiber (PF) synapses in cerebellum, neuronal glutamate transporters and metabotropic glutamate r eceptors (mGluRs) have overlapping postsynaptic distributions suggesting th at postsynaptic transporters selectively regulate mGluR activation. We exam ined interactions between transporters and mGluRs by evoking mGluR-mediated excitatory postsynaptic currents (mGluR EPSCs) in slices of rat cerebellum . Selective inhibition of postsynaptic transporters enhanced mGluR EPSCs gr eater than 3-fold. Moreover, impairing glutamate uptake facilitated mGluR-d ependent long-term depression at PF synapses. Our results demonstrate that uniquely positioned glutamate transporters strongly influence mGluR activat ion at cerebellar PF synapses. Postsynaptic glutamate uptake may serve as a general mechanism for regulating mGluR-initiated synaptic depression.