Several data have shown that the neural cell adhesion molecule (NCAM) is necessary for long-term memory formation and might play a role in the structural reorganization of synapses. The NCAM, encoded by a single gene, is represented by several isoforms that differ with regard to their content of alpha-2,8-linked sialic acid residues (PSA) on their extracellular domain. The carbohydrate PSA is known to promote plasticity, and PSA-NCAM isoforms remain expressed in the CA3 region of the adult hippocampus. In the present study, we investigated the effect on spatial memory consolidation of a PSA gain of function by injecting a PSA mimetic peptide (termed pr2) into the dorsal hippocampus. Mice were subjected to massed training in the spatial version of the water maze. Five hours after the last training session, experimental mice received an injection of pr2, whereas control mice received PBS or reverse peptide injections in the hippocampal CA3 region. Memory retention was tested at different time intervals: 24 h, 1 wk, and 4 wk. The results showed that the post-training infusion of pr2 peptide significantly increases spatial performance whenever it was assessed after the training phase. By contrast, administration of the control reverse peptide did not affect retention performance. These findings provide evidence that (1) PSA-NCAM is involved in memory consolidation processes in the CA3 hippocampal region, and (2) PSA mimetic peptides can facilitate the formation of long-term spatial memory when injected during the memory consolidation phase. (Contains 1 table and 4 figures.)