Abstract
Transporters act over wide ranges of time and space in the brain: they help prevent excitotoxicity by limiting tonic NMDA receptor activation, and in addition they maintain the specificity of neuronal communication by limiting spillover of synaptically released glutamate. In this work we show how small changes in transporter density can lead to supralinear changes in ambient extracellular glutamate, which may play a role in certain neuropathologies. In addition, we show data suggesting that the role of transporters in limiting NMDA receptor activity during synaptic transmission is complex and depends strongly on the frequency of synaptic activity. We show that in physiological conditions, Mg2+ block rather than glutamate transport plays a dominant role in restricting NMDA receptor activity during low frequency activity. During higher frequency activity, including frequency ranges associate with induction of long-term potentiation and learning, a pool of glutamate-bound and Mg2+-blocked NMDARs signal in a phase-shifted manner governed by glutamate transport.
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