Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength may underlie learning and memory in the brain. The induction of LTP occurs in postsynaptic cells in the hippocampal CA1 region but is presynaptic in CA3. LTD is also well characterized in CA1 but not in CA3. Low-frequency stimulation of mouse hippocampal slices caused homosynaptic LTD at the messy fiber-CA3 synapse, which may be induced presynaptically by activation of metabotropic glutamate receptors. Thus, the efficacy of messy fiber-CA3 synapses can be regulated bidirectionally, which may contribute to neuronal information processing.