The extracellular matrix is a complex network of macromolecules including glycoproteins, polysaccharides and proteoglycans. Tenascin-R and chondroitin sulfate proteoglycans are essential components of hippocampal extracellular matrix co-localised in perineuronal nets on interneurons. Mutant mice deficient in expression of tenascin-R showed a two-fold reduction of long-term potentiation induced by theta-burst stimulation of Schaffer collaterals in the stratum radiatum of the CA1 region of the hippocampus, as compared to wild-type mice. The same reduction in potentiation was observed in slices from wild-type mice pretreated for 2h with chondroitinase ABC that completely removed chondroitin sulfates from the extracellular matrix. Treatment of slices from tenascin-R deficient animals with the enzyme did not further reduce potentiation in comparison with untreated slices from these mice, showing an occlusion of effects produced by removal of tenascin-R and chondroitin sulfates. However, the level of potentiation recorded immediately after theta-burst stimulation was significantly higher in wild-type than in tenascin-R deficient mice, whereas chondroitinase ABC had no significant effect on this short-term form of plasticity. Enzymatic treatment also did not affect short-term depression evoked by low-frequency stimulation, whereas this form of synaptic plasticity was reduced in tenascin-R deficient mice. In contrast, long-term depression in CA1 was impaired by digestion of chondroitin sulfates but appeared normal in tenascin-R mutants. Our data demonstrate that tenascin-R and chondroitin sulfate proteoglycans differentially modulate several forms of synaptic plasticity, suggesting that different mechanisms are involved.