Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction

Although glutamate transporters maintain low extracellular levels of the ex citatory neurotransmitter glutamate in the nervous system, little is known about their roles in synaptic plasticity. Here, using knockout mice lacking GLT-1, that is the most abundant glial subtype of glutamate transporters, we showed that long-term potentiation (LTP) induced by tetanic stimulation in mutant mice was impaired in the hippocampal CA1 region. When tetanic sti mulation was applied in the presence of low concentrations of an N-methyl-D -aspartate (NMDA) receptor antagonist, the impairment was overcome. Consist ent with these results, the increased glutamate in the synaptic cleft of mu tant mice preferentially activated NMDA receptors. Furthermore, analyses of mutant mice revealed that the magnitude of NMDA receptor-dependent transie nt synaptic potentiation during low-frequency stimulation depended on the c oncentration of glutamate in the synaptic cleft. These findings suggest tha t GLT-1 plays critical roles in LTP induction, as well as in short-term pot entiation, through regulation of extracellular levels of glutamate, which e nables appropriate NMDA receptor activation.