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The Journal of Neuroscience, May 19, 2004, 24(20):4767-4777; doi:10.1523/JNEUROSCI.0364-04.2004

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Cellular/Molecular
NR2B-Containing Receptors Mediate Cross Talk among Hippocampal Synapses

Annalisa Scimemi,¹ Alan Fine,² Dimitri M. Kullmann,¹ and Dmitri A. Rusakov¹

¹Institute of Neurology, University College London, London WC1N 3BG, United Kingdom, and ²Division of Neurophysiology, National Institute for Medical Research, London NW7 1AA, United Kingdom

Under some conditions, synaptically released glutamate can exert long-range actions in the cortical microcircuitry. To what extent glutamate spillover leads to direct cross talk among individual synapses remains unclear. We recorded NMDAR-mediated EPSCs in acute hippocampal slices at 35°C by stimulating two independent pathways that converge on the same CA1 pyramidal cell. Activation of a conditioning pathway in the presence of the use-dependent blocker dizocilpine maleate (MK801) resulted in partial NMDA receptor (NMDAR) blockade in the other, silent pathway. This was accompanied by an increase in the rise time of the EPSCs in the conditioning (although not the silent) pathway, implying an increase in diffusional distance from release site to NMDARs. We estimated that up to 30% of NMDARs contributing to EPSCs were activated by glutamate released from multiple synaptic sources; however, NMDAR-mediated synaptic cross talk was undetectable when NR2B subunit-containing receptors were blocked (but could be rescued by blocking glutamate uptake). We propose that NR2B-containing NMDARs can detect glutamate arising from multiple synapses, whereas NR2A-containing NMDARs only normally mediate direct synaptic transmission. These NMDAR isoforms thus play complementary roles in sensing global and local glutamate signals, respectively.

Key words: hippocampus; glutamate; spillover; NMDA receptors; NR2B; synapse

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Received Feb 2, 2004; revised April 6, 2004; accepted April 6, 2004.

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