While the mechanisms responsible for LTP and LTD of excitatory synaptic responses mediated by AMPA receptors (AMPARs) have been extensively characterized, much less is known about the regulation of NMDA receptors (NMDARs) by synaptic activity. In hippocampal CA1 cells, prolonged low frequency afferent stimulation depresses synaptic responses mediated by either NMDARs or AMPARs. However, this apparently similar LTD is accompanied by a change in the coefficient of variation (CV) of only the AMPAR-mediated synaptic responses; the CV of the NMDAR-mediated synaptic responses is unaffected. Moreover, by varying the pattern of synaptic stimulation, the responses mediated by one receptor subtype can be modified without affecting the responses mediated by the other. These results indicate that the mechanisms underlying activity-dependent plasticity of NMDAR-mediated synaptic responses are different from those responsible for plasticity of AMPAR-mediated synaptic responses.