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 transporters in glial membranes restrict extrasynaptic diffusion, but it is unclear whether neuronal glutamate transporters also limit transmitter diffusion 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 those activated by spillover. Glutamate spillover is observed between Schaffer collateral fiber synapses onto CA1 pyramidal cells only when transporters in the postsynaptic neuron are inhibited. Because glutamate transporters operate most effectively at negative membrane potentials, these results suggest that activation of NMDA receptors by spillover may depend on postsynaptic activity.