The objective of this study was to examine the effect of carnosine on the hippocampal-dependent learning in perforant pathway/dentate gyrus synapses. The experiments were carried out on adult rats. A bipolar stimulating electrode was placed to the medial perforant path and a double-barrel glass micropipette was placed in the dentate gyrus as the recording electrode. Artificial cerebrospinal fluid (to control group) or carnosine (0.1, 1 mu g/mu L) was infused into the dentate gyrus via one of the barrels of the glass electrode. Our results showed that the I/O curve of excitatory postsynaptic potential (EPSP) slope or population spike (PS) amplitude was not significantly shifted by carnosine. Although carnosine infused prior to high-frequency stimulation (HFS) decreased the slope of EPSP and amplitude of PS, when infused after HFS, no effect was observed. In the present study, we speculated that carnosine decreased LTP by inhibiting sGC activation. The present experiment provides the first evidence that carnosine may play a role in synaptic plasticity in dentate gyrus in vivo.