Short-term depression strongly influences neuronal activity in cerebral circuits and contributes to low- pass temporal filtering of information. In this work, we show that synaptic depression evoked by stimulation of commissural/Schaffer collateral afferents at 10 Hz is associated with a reduction of the fibre volley. This depression of action potentials is also evident in the absence of extracellular Ca2+, which underlies its release-independent nature. In addition, this reduction of the excitability is independent of failures in action potential propagation since increasing the distance between the stimulus and recording electrodes does not alter this effect. Whole-cell recordings show that tetanic stimulation at supraminimal intensity induces action potential failures preceded by changes in the repolarization rate of the action potentials leading the membrane potential to hyperpolarized values. This activity-dependent hyperpolarization was blocked by ouabain, an indication of the important role of the Na+/K+-ATPase in this process. Then again, an alteration of the firing threshold was observed when action potentials were elicited either by somatic current injection or by synaptic stimulation, which indicates that this mechanism could alter the EPSP-spike coupling in these cells. The results suggest that these factors act together to reduce gradually the safety factor for action potential generation and to produce failures in action potential initiation; in fact, experiments made at twice the supraminimal intensity show a dramatic decrease in the rate of these failures. Taken together, the results suggest the existence of a release- independent component of short-term depression that is related to failures in action potential initiation.