Objective Melanocortin-4 receptor (MC4R), which belongs to the G-protein coupled receptor (GPCR) superfamily, is one of the five melanocortin receptors (MCRs) that is expressed abundantly in the central nervous system.MC4R is activated by various endogenous ligands including melanocyte stimulating hormone (MSH), and adrenocorticotropin hormones.The central melanocortin signaling in the hypothalamus-pituitary-adrenal axis system is critical for regulating various aspects of energy homeostasis and feeding behavior.Although MC4R is highly expressed in other brain regions such as cortex and hippocampus, the roles of MC4R in these regions remain elusive.In this study, the functional role of MC4R in synapse plasticity in hippocampus is examined.Methods The regulation of MC4R protein in hippocampal neurons was examined using immunocytochemical analysis and Western blot analysis.The function of MC4R in hippocampal neurons was studied by RNA interference using calcium phosphate transfection.Results (1) MC4R protein increases in rat hippocampus upon development and enriched at the synaptic compartment.(2) Knockdown of MC4R in cultured rat hippocampal neurons results in a regulation in the density of dendritic spines, the sites where excitatory synapses reside.(3) Stimulation of MC4R increases the cAMP level in hippocampal neurons.Conclusion MC4R regulates the synapse functions through modulating the morphology of dendritic spines.