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Transient NMDA Receptor Suppression Induces Long-Lasting Synaptic Depression

¹ University of California, Berkeley, California
² Marine Biological Laboratory, Woods Hole, Massachusetts

At many synapses, the induction of long-term synaptic modification requires NMDA receptor activation and corresponding Ca²⁺ influx into the postsynaptic cell (Zucker, 1999). We report here that, for layer 2/3 pyramidal neurons, transient suppression of NMDA receptor activity induces a long-term decrease in synaptic strength. Whole-cell recordings were made from the soma or apical dendrite of layer 2/3 pyramidal cells in slices of rat visual cortex. EPSPs were evoked with small bipolar electrodes placed in layer 2/3 near the apical dendrite of the cell under study. These synapses are highly enriched for NMDA receptors (Salin and Bullier, 1995), and NMDA receptor potentials (NMDAR-EPSPs) were isolated with CNQX, picrotoxin, and 1.5 mM [Mg²⁺]_o. We observed that pairing a single action potential (AP) with a subsequent NMDAR-EPSP led to an immediate reduction in the NMDAR-EPSP amplitude within a short time window (<100 ms), correlating with the time window for induction of spike-timing-dependent long-term depression (LTD) of EPSPs at these synapses. NMDAR-EPSP suppression and LTD have a similar pharmacological profile, and both are reduced or blocked by nimodipine, calcineurin inhibitory peptide, cyclosporin A, and internal BAPTA. Additionally, we found that long-lasting depression of synaptic strength could be induced in the absence of postsynaptic spiking by a temporary wash-in of either low doses of APV (2–4 µM) or an increase in [Mg²⁺]_o (6 mM). In contrast, temporary wash-in of 0 mM [Mg²⁺]_o produced a long-lasting enhancement of synaptic strength. These results suggest that the amount of NMDA receptor activation, and thus postsynaptic Ca²⁺ influx, is a critical determinant of sign and magnitude of long-term synaptic plasticity. For layer 2/3 synapses in particular, we propose a model in which basal synaptic transmission leads to an intermediate level of Ca²⁺ influx between the levels required for LTD or long-term potentiation.

RCF is supported by the Grass Foundation and the Howard Hughes Medical Institute. YD is supported by the National Eye Institute.

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Froemke, R. C. Articles by Yang, D. Search for Related Content PubMed Articles by Froemke, R. C. Articles by Yang, D.