Down syndrome (DS) patients who show mental retardation also present acquired anosmia, i.e., the loss of odor detection. At the present time, no viable treatment exists for cognitive and olfactory deficits in DS. Interestingly, the ability to reach puberty and become fertile is also affected in these patients. An intriguing candidate, whose absence could mediate most of these phenotypes, is the gonadotropin-releasing hormone (GnRH), the neurohormone controlling reproduction. However, whether GnRH plays a role in the age-related cognitive decline in DS is unknown.We showed in Ts65dn mice, a well characterized DS mouse model, that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic expression of GnRH and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation. Particularly, the miR-200 family was downregulated in the hypothalamus of Ts65Dn mice, while Zeb1 and Cebpb expression, two important repressors of the Gnrh promoter, were increased. Epigenetic and pharmacological interventions that restore physiological GnRH levels, as well as the hypothalamic overexpression of miR-200b, resulted in a rescue of olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improved cognition and brain connectivity in adult DS patients.GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.These results have been published recently in Science (Manfredi-Lozano et al., 2022, doi: 10.1126/science.abq4515).