作者
Maria Manfredi-Lozano,Valerie Leysen,Michela Adamo,Isabel Paiva,Renaud Rovera,Jean-Michel Pignat,Fatima Ezzahra Timzoura,Michael Candlish,Sabiha Eddarkaoui,Samuel A. Malone,Mauro S. B. Silva,Sara Trova,Monica Imbernon,Laurine Decoster,Ludovica Cotellessa,M. Tena-Sempere,Marc Claret,Ariane Paoloni-Giacobino,Damien Plassard,Emmanuelle Paccou,Kathryn J Burton,James Acierno,Aleksandra Maceski,Antoine Lutti,Frank W. Pfrieger,Sowmyalakshmi Rasika,Federico Santoni,Ulrich Boehm,Philippe Ciofi,Luc Buée,Nasser Haddjeri,Anne-Laurence Boutillier,Jens Kuhle,Andrea Messina,Bogdan Draganski,Paolo Giacobini,N. Pitteloud,Vincent Prevot
摘要
At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction—gonadotropin-releasing hormone (GnRH)—and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves 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.