Neuronal glutamate transporters limit activation of NMDA receptors by neurotransmitter spillover on CA1 pyramidal cells

Glutamate released at synapses in the CA1 region of the hippocampus escapes the synaptic cleft and activates extrasynaptic targets; it also may "spill over" into neighboring synapses and activate receptors there. Glutamate tr ansporters in glial membranes restrict extrasynaptic diffusion, but it is u nclear whether neuronal glutamate transporters also limit transmitter diffu sion and receptor activation by spillover. I examined the effects of a low- affinity competitive NMDA receptor antagonist on EPSCs in acute hippocampal slices to distinguish receptors activated within active synapses from thos e activated by spillover. Glutamate spillover is observed between Schaffer collateral fiber synapses onto CA1 pyramidal cells only when transporters i n the postsynaptic neuron are inhibited. Because glutamate transporters ope rate most effectively at negative membrane potentials, these results sugges t that activation of NMDA receptors by spillover may depend on postsynaptic activity.