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

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.