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Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses

Nature Neuroscience volume 8, pages 1043–1050 (2005)Cite this article

Abstract

Although long-term depression (LTD) of AMPA receptor–mediated postsynaptic currents (AMPAR EPSCs) has been extensively examined, little is known about the mechanisms responsible for LTD of NMDA receptor (NMDAR)-mediated EPSCs. Here we show differences in the intracellular signaling cascades that mediate LTD of AMPAR EPSCs versus NMDAR EPSCs in rat hippocampus. Both forms of LTD were blocked by inhibitors of protein phosphatase 1, but only LTD of AMPAR EPSCs was affected by inhibition of calcineurin. Notably, in contrast to LTD of AMPAR EPSCs, LTD of NMDAR EPSCs was unaffected by endocytosis inhibitors. A role for calcium-dependent actin depolymerization in LTD of NMDAR EPSCs was supported by the findings that the actin stabilizer phalloidin and a cofilin inhibitory peptide each blocked LTD of NMDAR EPSCs but not AMPAR EPSCs. These results suggest that the same pattern of afferent activity elicits depression of AMPAR- and NMDAR-mediated synaptic responses by means of distinct triggering and expression mechanisms.

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Figure 1: LTD of NMDAR-mediated synaptic transmission at Schaffer collateral–CA1 synapses is Ca2+-dependent and requires activation of NMDARs and not mGluRs.
Figure 2: Protein phosphatase 1/2A inhibitors block LTD of NMDAR EPSCs.
Figure 3: The protein phosphatase 2B (calcineurin) inhibitor FK-506 blocks LTD of AMPAR EPSCs but not LTD of NMDAR EPSCs.
Figure 4: LTD of NMDAR EPSCs is not blocked by inhibitors of dynamin-dependent endocytosis.
Figure 5: In vivo expression of a dominant-negative form of dynamin blocks LTD of AMPAR EPSCs but not LTD of NMDAR EPSCs.
Figure 6: LTD of NMDAR EPSCs is blocked by the actin stabilizing agent, phalloidin, and a peptide that inhibits cofilin.
Figure 7: Dual-component EPSCs demonstrate selective block of LTD of either AMPAR or NMDAR components by D15 and phalloidin, respectively.
Figure 8: Graph summarizing the effects of all of the experimental manipulations on LTD of NMDAR EPSCs and LTD of AMPAR EPSCs.

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Acknowledgements

We thank S.Y. Lee for technical assistance and members of the Malenka lab for constructive comments. This work was supported by US National Institutes of Health grant MH063394 to R.C.M.

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  1. Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University School of Medicine, 1201 Welch Rd., Palo Alto, 94304, California, USA

    Wade Morishita, Helene Marie & Robert C Malenka

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Correspondence to Robert C Malenka.

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Supplementary information

Supplementary Fig. 1

Schematic diagram illustrating working model of the different signal transduction pathways involved in LTD of AMPAR EPSCs and LTD of NMDAR EPSCs. (PDF 907 kb)

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Morishita, W., Marie, H. & Malenka, R. Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses. Nat Neurosci 8, 1043–1050 (2005). https://doi.org/10.1038/nn1506

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