Glutamate transporters are responsible for clearing synaptically released glutamate from the extracellular space. If expressed at high enough densities, transporters can prevent activation of extrasynaptic receptors by rapidly lowering glutamate concentrations to insignificant levels. We find that synaptic activation of metabotropic glutamate receptors expressed by Purkinje cells is prevented in regions of rat cerebellum where the density of the glutamate transporter EAAT4 is high. The consequences of metabotropic receptor stimulation, including activation of a depolarizing conductance, cannabinoid-mediated presynaptic inhibition and long-term depression, are also limited in Purkinje cells expressing high levels of EAAT4. We conclude that neuronal uptake sites must be overwhelmed by glutamate to activate perisynaptic metabotropic glutamate receptors. Regional differences in glutamate transporter expression affect the degree of metabotropic glutamate receptor activation and therefore regulate synaptic plasticity. © 2005 Nature Publishing Group.