We investigated the behavior of mice deficient for the extracellular matrix (ECM) glycoprotein tenascin-R (TN-R) in comparison to their wild-type (WT) littermates. A longitudinal study including tests for exploration and anxiety, motor coordination and cognition was carried out. Mice were tested at different ages, ranging from 3 weeks to 11 months and under different housing conditions. TN-R deficient mice displayed decreased motivation to explore and an increased anxiety profile in the free choice open field (FCOF), open field (OF) and elevated plus maze (EPM) tests. Moreover, the anxiety level of TN-R deficient mice was more strongly influenced by environmental factors as compared to WT littermates. TN-R deficient mice showed motor coordination impairments in the wire hanging, Rotarod and pole test. Thus TN-R ablation leads to an altered behavioral phenotype in mice that may negatively affect their fitness under natural conditions.