1. Paired intracellular recordings were performed in slices of adult rat neocortex and hippocampus to examine presynaptic depression. A novel form of depression that occurs even in the absence of transmitter release during conditioning activity was observed at a subset of synaptic connections. 2. In each pair studied, a pyramidal neurone was presynaptic and inputs onto a range of morphologically identified postsynaptic target cells were analysed; high probability connections exhibiting the more traditional forms of release-dependent depression, as well as low probability connections exhibiting facilitation, were tested (n = 35). 3. Connections were tested with presynaptic spike pairs and trains of spikes with a range of interspike intervals. Sweeps in which the first action potential elicited no detectable response (apparent failures of transmission) and sweeps in which the first action potential elicited large EPSPs were selected. Second EPSPs that followed apparent failures were then compared with second EPSPs that followed large first EPSPs. 4. Release-independent depression was apparent when second EPSPs at brief interspike intervals (<10-15 ms) were on average smaller than second EPSPs at longer interspike intervals, even following apparent failures and when the second EPSP amplitude at these short intervals was independent of the amplitude of the first EPSP. 5. Release-independent depression appeared selectively expressed. Depressing inputs onto some interneurones, such as CA1 basket-like and bistratified cells, and facilitating inputs onto others, such as some fast spiking neocortical interneurones, exhibited this phenomenon. In contrast, depressing inputs onto 10/10 neocortical pyramids and facilitating inputs onto 7/7 oriens-lacunosum moleculare and 5/5 burst firing, sparsely spiny neocortical interneurones did not.