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Down syndrome is the most common genetic cause of intellectual disability. Nevertheless, under certain stimulation processes, Down syndrome people can develop certain intellectual skills, suggesting an active mechanism of neuronal plasticity. Defects in both dendritic arborization and dendritic spines could affect neuronal plasticity and contribute to the degree of intellectual disability in people with Down syndrome. However, the cellular mechanisms involved in this process are unknown. Thrombospondin-1 (TSP-1) is an astrocyte-secreted protein involved in the development and maintenance of dendritic spines and synapses, which is altered in Down syndrome. Nonetheless, the role of TSP-1 in neuronal plasticity is not well characterized. In this study, we analyze whether TSP-1 is involved in neuronal microstructure changes induced by environmental enrichment, a model of experience-dependent neuronal plasticity. We found that the increase in dendritic spine density induced by environmental enrichment is associated with an increase in TSP-1 levels in the hippocampus of wild-type mice. The lack of TSP-1 in TSP-1^-/- mice produce changes in the number and length of dendritic branches and a decrease in both, the number of intersections and density of dendritic spines. Exposure of TSP-1^-/- mice to environmental enrichment did not affect the dendritic length and branching and number of intersections, but increased the density of dendritic spines significantly. These results suggest a role of TSP-1 as an important factor regulating brain microstructural plasticity, whose activity is reduced in Down syndrome.