Fast chemical synapses mediate rapid communications between neurons. Interestingly, the strength of most synapses is not constant but dynamic, depending on the history of presynaptic activity. In many cases, repetitive activation of presynaptic neurons leads to a rapid decrease in synaptic strength, a phenomenon termed short-term depression. In this study, two synapses that exhibit profound short-term depression were investigated: a glycinergic inhibitory synapse in the auditory brainstem and a glutamatergic excitatory synapse in the cerebellum. The mechanisms underlying short-term depression at these two synapses are strikingly different, and consequently have distinct impacts at cellular or microcircuit level.