The number of vesicles contained in the readily releasable pool at excitatory hippocampal synapses has recently been identified as a major determinant of the strength of these synapses. Here, we show that the rate at which this pool refills following depletion is variable from neuron to neuron and can be increased by the accumulation of intracellular calcium during action potential-mediated activation of the synapses. The refilling rate nearly doubles during the first second of a high frequency train of action potentials and does not increase further with additional stimulation. During periods of rest, the rate relaxes back to its original value, with a time constant of about 10 s. Since this refilling rate helps set the strength of synapses during high frequency bursts of action potentials and is modulated by physiological signaling, it is an attractive candidate point of control in the storage and manipulation of information by the central nervous system.