A recent study revealed that normalization of the Dyrk1A expression level exclusively in the hippocampus by injecting a viral vector containing inhibitory Dyrk1A shRNA did not improve the learning abilities of TS mice; however, this intervention enhanced their search strategy during the MWM test. The Trifluoperazine dihydrochloride discrepancy between these results and the partial rescue of the performance on the MWM test found in the present study may be explained by the tissues in which Dyrk1A expression was normalized in each study. The reference and working memory components and the longterm consolidation process in the spatial learning component of the MWM test are dependent on the integrity of not only the hippocampus but also the prefrontal cortex, which is a structure that is also affected in DS. In this study, the Dyrk1A gene dosage was also normalized in the cortex and, U-104 presumably, in all tissues in which Dyrk1A is overexpressed. Therefore, Dyrk1A normalization may result in more efficient learning. Additional support for the role of Dyrk1A in the altered cognitive abilities found in DS mouse models comes from studies demonstrating that the pharmacological inhibition of this gene using epigallocatechin gallate, improves hippocampaldependent learning and thigmotaxis in TgDyrk1A and Ts65Dn mice. In addition, in a pilot clinical trial of individuals with DS, administration of EGCG enhanced their accuracy in visual memory recognition and spatial working memory, suggesting a positive effect of this compound on the prefrontal system. Interestingly, a recent report implicated Dyrk1A overexpression in the structural and functional anomalies of the prefrontal cortex. Therefore, the cognition-enhancing effects of normalization of the Dyrk1A expression level may be due to its effects on the hippocampal-prefrontal functional networks that support memoryrelated functions. Hox genes encode evolutionarily conserved transcription factors that control the formation of body segment-specific structures by regulating the transcription of downstream effectors that, in turn, direct the morphogenetic events leading to the complex body forms along the embryonic axes in metazoan.