High frequency stimulation of pyramidal cell inputs to developing (P9-12) hippocampal st. radiatum interneurons expressing GluR2-lacking, Ca²⁺-permeable AMPA receptors produces long-term depression of synaptic transmission, if NMDA receptors are blocked (Laezza et al., Science 285: 1411, 1999). Here we show that these same synapses display a remarkably versatile signal integration if postsynaptic NMDA receptors are activated. At synapses expressing GluR2-deficient AMPA receptors, tetanic stimulation that activates NMDA receptors triggered LTP or LTD depending on membrane potential. LTP was elicited at most synapses when the interneuron was held at -30 mV during the stimulus train, but was typically prevented by postsynaptic hyperpolarization to -70 mV, by strong depolarization to 0 mV, by D-APV, or by postsynaptic injection of the Ca²⁺ chelator BAPTA. At synapses with predominantly GluR2-containing AMPA receptors, repetitive stimulation did not change synaptic strength regardless of whether NMDA receptors were activated. The interactions among GluR2 expression, NMDA receptor expression and membrane potential thus confer upon hippocampal interneurons a distinctive means for differential decoding of high frequency inputs, resulting in enhanced or depressed transmission depending upon the functional state of the interneuron.