GnRH replacement rescues cognition in Down syndrome
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Michela Adamo
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Isabel Paiva
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Renaud Rovera
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Sabiha Eddarkaoui
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Samuel Malone
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Mauro Silva
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Sara Trova
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Ludovica Cotellessa
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Manuel Tena-Sempere
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Marc Claret
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Ariane Paoloni-Giacobino
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Damien Plassard
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Nathalie Vionnet
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Aleksandra Maleska Maceski
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Antoine Lutti
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Frank Pfrieger
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S. Rasika
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Federico Santoni
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Ulrich Boehm
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Luc Buée
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Andrea Messina
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Bogdan Draganski
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Paolo Giacobini
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Nelly Pitteloud
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Vincent Prevot
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Abstract
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.