At many glutamatergic synapses in the brain, calcium-permeable alpha - amino - 3 - hydro - 5 - methyl - 4 - isoxazolepropionate receptor (AMPAR) channels mediate fast excitatory transmission. These channels are blocked by endogenous intracellular polyamines, which are found in virtually every type of cell. In excised patches, use-dependent relief of polyamine block enhances glutamate-evoked currents through recombinant and native calcium-permeable, polyamine-sensitive AMPAR channels. The contribution of polyamine unblock to synaptic currents during high-frequency stimulation may be to facilitate currents and maintain current amplitudes in the face of a slow recovery from desensitization or presynaptic depression. Here we show, on pairs and triples of synaptically connected neurons in slices, that this mechanism contributes to short-term plasticity in local circuits formed by presynaptic pyramidal neurons and postsynaptic multipolar interneurons in layer 2/3 of rat neocortex. Activity-dependent relief from polyamine block of postsynaptic calcium-permeable AMPARs in the interneurons either reduces the rate of paired-pulse depression in a frequency-dependent manner or, at a given stimulation frequency, induces facilitation of a synaptic response that would otherwise depress. This mechanism for the enhancement of synaptic gain appears to be entirely postsynaptic.