GnRH replacement rescues cognition in Down syndrome

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 expressio...

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Published in:Science (American Association for the Advancement of Science) 2022-09, Vol.377 (6610), p.eabq4515-eabq4515
Main Authors: Manfredi-Lozano, Maria, Leysen, Valerie, Adamo, Michela, Paiva, Isabel, Rovera, Renaud, Pignat, Jean-Michel, Timzoura, Fatima Ezzahra, Candlish, Michael, Eddarkaoui, Sabiha, Malone, Samuel A, Silva, Mauro S B, Trova, Sara, Imbernon, Monica, Decoster, Laurine, Cotellessa, Ludovica, Tena-Sempere, Manuel, Claret, Marc, Paoloni-Giacobino, Ariane, Plassard, Damien, Paccou, Emmanuelle, Vionnet, Nathalie, Acierno, James, Maceski, Aleksandra Maleska, Lutti, Antoine, Pfrieger, Frank, Rasika, S, Santoni, Federico, Boehm, Ulrich, Ciofi, Philippe, Buée, Luc, Haddjeri, Nasser, Boutillier, Anne-Laurence, Kuhle, Jens, Messina, Andrea, Draganski, Bogdan, Giacobini, Paolo, Pitteloud, Nelly, Prevot, Vincent
Format: Article
Language:English
Subjects:
Adult
Adults
Age
Animal models
Animals
Brain
Chromosome 21
Chromosomes
Clinical trials
Cognition
Cognition & reasoning
Cognition - drug effects
Cognition - physiology
Cognitive ability
Cognitive Dysfunction - drug therapy
Cognitive Dysfunction - etiology
Defects
Disease Models, Animal
Down syndrome
Down Syndrome - complications
Down Syndrome - drug therapy
Down Syndrome - psychology
Down's syndrome
Female
Fertility
Functional anatomy
Gene expression
Gonadotropin-releasing hormone
Gonadotropin-Releasing Hormone - pharmacology
Gonadotropin-Releasing Hormone - physiology
Gonadotropin-Releasing Hormone - therapeutic use
Gonadotropins
Health services
Hippocampus
Humans
Hypothalamus
Hypothalamus - drug effects
Hypothalamus - metabolism
Infertility
Kallmann's syndrome
Life Sciences
Luteinizing hormone
Male
Maturation
Mice
MicroRNAs
Middle Aged
Myelination
Neural networks
Neurons
Neurons and Cognition
Olfaction
Olfaction Disorders - drug therapy
Olfaction Disorders - etiology
Patients
Physiology
Pituitary (anterior)
Puberty
Ribonucleic acid
RNA
Secretion
Signs and symptoms
Synaptic transmission
Synaptic Transmission - drug effects
Therapy
Transcription factors
Young Adult
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Summary: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.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.abq4515