GnRH replacement rescues cognition in Down syndrome-Reference-Cited by-同舟云学术

GnRH replacement rescues cognition in Down syndrome

Published:2022-09-02 Issue:6610 Volume:377 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Manfredi-Lozano Maria¹²^ORCID,Leysen Valerie¹²,Adamo Michela³⁴^ORCID,Paiva Isabel⁵^ORCID,Rovera Renaud⁶^ORCID,Pignat Jean-Michel⁷,Timzoura Fatima Ezzahra¹²^ORCID,Candlish Michael⁸,Eddarkaoui Sabiha¹^ORCID,Malone Samuel A.¹²^ORCID,Silva Mauro S. B.¹²^ORCID,Trova Sara¹²^ORCID,Imbernon Monica¹²,Decoster Laurine¹²,Cotellessa Ludovica¹²^ORCID,Tena-Sempere Manuel⁹^ORCID,Claret Marc¹⁰¹¹^ORCID,Paoloni-Giacobino Ariane¹²^ORCID,Plassard Damien¹³^ORCID,Paccou Emmanuelle³,Vionnet Nathalie³^ORCID,Acierno James³,Maceski Aleksandra Maleska¹⁴^ORCID,Lutti Antoine¹⁵^ORCID,Pfrieger Frank¹⁶^ORCID,Rasika S.¹²^ORCID,Santoni Federico⁴^ORCID,Boehm Ulrich⁸^ORCID,Ciofi Philippe¹⁷,Buée Luc¹^ORCID,Haddjeri Nasser⁶,Boutillier Anne-Laurence⁵^ORCID,Kuhle Jens¹⁴,Messina Andrea³⁴^ORCID,Draganski Bogdan¹⁵¹⁸^ORCID,Giacobini Paolo¹²^ORCID,Pitteloud Nelly³⁴^ORCID,Prevot Vincent¹²^ORCID

Affiliation:

1. Univ. Lille, Inserm, CHU Lille, Lille Neuroscience and Cognition, UMR-S 1172, Labex DistAlz, Lille, France.

2. Laboratory of Development and Plasticity of the Neuroendocrine Brain, FHU 1000 Days for Health, EGID, Lille, France.

3. Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland.

4. Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

5. Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364, Université de Strasbourg-CNRS, Strasbourg, France.

6. Université de Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.

7. Department of Clinical Neurosciences, Neurorehabilitation Unit, University Hospital CHUV, Lausanne, Switzerland.

8. Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany.

9. Universidad de Córdoba, IMIBC/HURS, CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Córdoba, Spain.

10. Neuronal Control of Metabolism Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

11. Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.

12. Department of Genetic Medicine, University Hospitals of Geneva, Genève, Switzerland.

13. CNRS UMR 7104, INSERM U1258, GenomEast Platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.

14. Neurologic Clinic and Polyclinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland.

15. Laboratory for Research in Neuroimaging (LREN), Centre for Research in Neurosciences, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

16. Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.

17. Université de Bordeaux, Inserm, U1215, Neurocentre Magendie, Bordeaux, France.

18. Neurology Department, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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