In tests of spatial ability males outperform females. The mechanism underlying this gender differential learning ability and memory in spatial tasks remain unknown. The aim of this work was to assess whether differences between male and female rats in spatial learning are associated with differences in basal synaptic activity and in LTP in hippocampus and to identify the molecular mechanisms responsible for the gender differences in LTP. We analyzed in young male and female rats: a) performance in spatial tasks in the Radial and Morris water mazes; b) basal synaptic activity in hippocampal slices; c) LTP and some mechanisms modulating its magnitude. Female rats show larger AMPA receptor-mediates synaptic responses under basal conditions, likely due to enhanced phosphorylation of GluR2 in Ser880 and increased amount of GluR2-containing AMPA receptors in post-synaptic densities. In contrast, the magnitude of tetanus-induced LTP was lower in females than in males. This is due to reduced activation of soluble guanylate cyclase and formation of cGMP, leading to lower activation of cGMP-dependent protein kinase and phosphorylation of GluR1 in Ser845, which results in lower insertion of AMPA receptors in the synaptic membrane and a lower magnitude of LTP. These mechanisms would be involved in the reduced performance of females in the radial and Morris water mazes.