GnRH replacement rescues cognition in Down syndrome
Maria Manfredi-Lozano
(1, 2, 3, 4, 5)
,
Valerie Leysen
(1, 2, 3, 4, 5)
,
Michela Adamo
(6, 7)
,
Isabel Paiva
(8)
,
Renaud Rovera
(9)
,
Jean-Michel Pignat
(10)
,
Fatima Ezzahra Timzoura
(1, 2, 3, 4, 5)
,
Michael Candlish
(11)
,
Sabiha Eddarkaoui
(1, 2, 3)
,
Samuel Malone
(1, 2, 3, 4, 5)
,
Mauro Silva
(1, 2, 3, 4, 5)
,
Sara Trova
(1, 2, 3, 4, 5)
,
Monica Imbernon
(1, 2, 3, 4, 5)
,
Laurine Decoster
(1, 2, 3, 4, 5)
,
Ludovica Cotellessa
(1, 2, 3, 4, 5)
,
Manuel Tena-Sempere
(12)
,
Marc Claret
(13, 14)
,
Ariane Paoloni-Giacobino
(15)
,
Damien Plassard
(16)
,
Emmanuelle Paccou
(6)
,
Nathalie Vionnet
(6)
,
James Acierno
(6)
,
Aleksandra Maleska Maceski
(17, 18)
,
Antoine Lutti
(6, 7)
,
Frank Pfrieger
(19)
,
S. Rasika
(1, 2, 3, 4, 5)
,
Federico Santoni
(7)
,
Ulrich Boehm
(11)
,
Philippe Ciofi
(20)
,
Luc Buée
(1, 2, 3)
,
Nasser Haddjeri
(9)
,
Anne-Laurence Boutillier
(8)
,
Jens Kuhle
(17, 18)
,
Andrea Messina
(6, 7)
,
Bogdan Draganski
(6, 7, 21)
,
Paolo Giacobini
(1, 2, 3, 4, 5)
,
Nelly Pitteloud
(6, 7)
,
Vincent Prevot
(2, 1, 3, 4, 5)
1
CHU Lille
2 LilNCog - Lille Neurosciences & Cognition - U 1172
3 Excellence Laboratory LabEx DISTALZ
4 FHU 1,000 Days for Health [Lille]
5 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
6 Lausanne University Hospital
7 UNIL - Université de Lausanne = University of Lausanne
8 LNCA - Laboratoire de neurosciences cognitives et adaptatives
9 U1208 Inserm - UCBL1 / SBRI - USC 1361 INRAE - Institut cellule souche et cerveau / Stem Cell and Brain Research Institute
10 CHUV - Centre Hospitalier Universitaire Vaudois [Lausanne]
11 Saarland University [Saarbrücken]
12 ISC - Instituto de Salud Carlos III [Madrid]
13 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
14 CIBERDEM - Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas
15 HUG - Hôpital Universitaire de Genève = University Hospitals of Geneva
16 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
17 University Hospital Basel [Basel]
18 Unibas - University of Basel
19 INCI - Institut des Neurosciences Cellulaires et Intégratives
20 U1215 Inserm - UB - Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale
21 IMPNSC - Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig]
2 LilNCog - Lille Neurosciences & Cognition - U 1172
3 Excellence Laboratory LabEx DISTALZ
4 FHU 1,000 Days for Health [Lille]
5 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
6 Lausanne University Hospital
7 UNIL - Université de Lausanne = University of Lausanne
8 LNCA - Laboratoire de neurosciences cognitives et adaptatives
9 U1208 Inserm - UCBL1 / SBRI - USC 1361 INRAE - Institut cellule souche et cerveau / Stem Cell and Brain Research Institute
10 CHUV - Centre Hospitalier Universitaire Vaudois [Lausanne]
11 Saarland University [Saarbrücken]
12 ISC - Instituto de Salud Carlos III [Madrid]
13 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
14 CIBERDEM - Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas
15 HUG - Hôpital Universitaire de Genève = University Hospitals of Geneva
16 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
17 University Hospital Basel [Basel]
18 Unibas - University of Basel
19 INCI - Institut des Neurosciences Cellulaires et Intégratives
20 U1215 Inserm - UB - Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale
21 IMPNSC - Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig]
Maria Manfredi-Lozano
- Function : Author
- PersonId : 1165203
- ORCID : 0000-0003-3801-1955
Michela Adamo
- Function : Author
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- ORCID : 0000-0002-9994-0945
Isabel Paiva
- Function : Author
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Renaud Rovera
- Function : Author
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Fatima Ezzahra Timzoura
- Function : Author
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- ORCID : 0000-0002-0499-9785
Sabiha Eddarkaoui
- Function : Author
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- ORCID : 0000-0002-5057-9335
Manuel Tena-Sempere
- Function : Author
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- ORCID : 0000-0002-4741-5567
Marc Claret
- Function : Author
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- ORCID : 0000-0001-7766-9296
Ariane Paoloni-Giacobino
- Function : Author
- PersonId : 1165214
- ORCID : 0000-0001-9432-1785
Damien Plassard
- Function : Author
- PersonId : 797234
- ORCID : 0000-0001-8569-6163
Nathalie Vionnet
- Function : Author
- PersonId : 1165215
- ORCID : 0000-0002-5420-8216
Aleksandra Maleska Maceski
- Function : Author
- PersonId : 1165216
- ORCID : 0000-0002-1916-5927
Antoine Lutti
- Function : Author
- PersonId : 1165217
- ORCID : 0000-0003-3281-5477
Frank Pfrieger
- Function : Author
- PersonId : 740924
- IdHAL : frank-pfrieger
- ORCID : 0000-0001-7085-1431
- IdRef : 102417091
Federico Santoni
- Function : Author
- PersonId : 1165218
- ORCID : 0000-0002-3258-4747
Ulrich Boehm
- Function : Author
- PersonId : 1165219
- ORCID : 0000-0003-2436-6907
Luc Buée
- Function : Author
- PersonId : 173203
- IdHAL : luc-buee
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- IdRef : 075014068
Andrea Messina
- Function : Author
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Bogdan Draganski
- Function : Author
- PersonId : 792525
- ORCID : 0000-0002-5159-5919
Paolo Giacobini
- Function : Author
- PersonId : 767534
- ORCID : 0000-0002-3075-1441
- IdRef : 182894541
Nelly Pitteloud
- Function : Author
- PersonId : 1165221
- ORCID : 0000-0003-0971-3237
Vincent Prevot
- Function : Author
- PersonId : 760908
- ORCID : 0000-0001-7185-3615
- IdRef : 076189279
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.