Abstract The pineal product melatonin that acts on specific melatonin receptors has been implicated in pathobiological mechanisms of neuropsychiatric disorders including Alzheimer's disease. We used mice lacking melatonin MT 2 receptors (MT 2 knockouts) to investigate the role of these receptors in synaptic plasticity and learning-dependent behavior. In field CA1 of hippocampal slices from wild-type mice, theta burst stimulation induced robust and stable long-term potentiation that was smaller and decremental in slices from MT 2 knockouts. Tested in an elevated plus-maze on two consecutive days, wild-type mice showed shorter transfer latencies to enter a closed arm on the second day; this experience-dependent behavior did not occur in MT 2 knockouts. These results suggest that MT 2 receptors participate in hippocampal synaptic plasticity and in memory processes.