Epigenetic changes of the chromatin, such as histone acetylation, represent an attractive molecular substrate for long-term memory and other forms of adaptation to the environment. We will discuss here the role of CBP, a histone acetyltransferase involved in mental retardation, in neuronal viability and plasticity using different strains of genetically modified mice. Our studies in forebrain-restricted CBP mutants show that the loss of this protein in forebrain principal neurons causes modest memory and transcriptional defects and a dramatic reduction of histone acetylation, but does not affect cell viability. In another line of research, morphological and behavioral analyses on cbp+/- mice demonstrate that environmental enrichment (EE) can ameliorate some deficits associated to CBP-deficiency, but these mice still show a strong defect in environment-induced neurogenesis that correlates with attenuation of the transcriptional program associated with this process and with impaired EE-enhanced spatial navigation. Overall, our experiments provide novel insights into the etiology of Rubinstein-Taybi mental retardation, clarify some of the standing questions concerning the role of CBP and histone acetylation in activity-driven gene expression, memory formation and neurodegeneration, and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics.