GnRH replacement rescues cognition in Down syndrome

  • Science. 2022 Sep 2;377(6610):eabq4515. doi: 10.1126/science.abq4515.
Maria Manfredi-Lozano  #  1  2 Valerie Leysen  #  1  2 Michela Adamo  #  3  4 Isabel Paiva  5 Renaud Rovera  6 Jean-Michel Pignat  7 Fatima Ezzahra Timzoura  1  2 Michael Candlish  8 Sabiha Eddarkaoui  1 Samuel A Malone  1  2 Mauro S B Silva  1  2 Sara Trova  1  2 Monica Imbernon  1  2 Laurine Decoster  1  2 Ludovica Cotellessa  1  2 Manuel Tena-Sempere  9 Marc Claret  10  11 Ariane Paoloni-Giacobino  12 Damien Plassard  13 Emmanuelle Paccou  3 Nathalie Vionnet  3 James Acierno  3 Aleksandra Maleska Maceski  14 Antoine Lutti  15 Frank Pfrieger  16 S Rasika  1  2 Federico Santoni  4 Ulrich Boehm  8 Philippe Ciofi  17 Luc Buée  1 Nasser Haddjeri  6 Anne-Laurence Boutillier  5 Jens Kuhle  14 Andrea Messina  3  4 Bogdan Draganski  15  18 Paolo Giacobini  #  1  2 Nelly Pitteloud  #  3  4 Vincent Prevot  #  1  2
Affiliations
  • 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.
  • # Contributed equally.
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.