In the present study, electrophysiological recordings were made from hippocampal slices obtained from mice overexpressing galanin under the promoter for the platelet-derived growth factor-B (GalOE mice). In these mice, a particularly strong galanin expression is seen in the granule cell layer/mossy fibers. Paired-pulse facilitation (PPF) of excitatory postsynaptic field potentials (fEPSPs) at the lateral perforant path (LPP)-dentate gyrus synapses was elicited in the dentate gyrus after stimulation with different interpulse intervals. Slices from young adult wild-type (WT) animals showed significant PPF of the 2nd EPSP evoked with paired-pulse stimuli, while PPF was reduced in slices from young adult GalOE mice, as well as aged WT mice, but were not observed at all in slices from aged GalOE animals. Application of the putative galanin antagonist M35 increased PPF in slices from aged WT mice as well as from adult and aged GalOE mice, but had no effect in slices taken from young adult WT mice. These data indicate that galanin is involved in hippocampal synaptic plasticity, in particular in age-related reduction of synaptic plasticity in the LPP input to the dentate gyrus. Galaninergic mechanisms may therefore represent therapeutic targets for treatment of age-related memory deficits and Alzheimer's disease.