The present study examined the role of N-methyl-d-aspartic acid (NMDA) receptors in synaptic plasticity in regular-spiking cells of rat frontal cortex. Intracortical stimulation, at levels subthreshold for elicitation of action potentials, evoked a late excitatory postsynaptic potential (EPSP) in layer II III neurons that was sensitive to the selective NMDA antagonist d-2-amino-5-phosphonovaleric acid (APV). This late EPSP showed marked short-term frequency-dependent depression, suggesting that it is polysynaptic in origin. Polysynaptic late EPSPs were selectively enhanced following high-frequency stimulation. This sustained increase in synaptic efficacy, or long-term potentiation, was expressed in regular spiking cells and appeared to result from activation of NMDA receptors on excitatory interneurons. These data demonstrate the existence of an NMDA-modulated polysynaptic circuit in the neocortex which displays several types of use-dependent plasticity. © 1989.