GnRH Secreting Neuron Dysfunction Identified in Down Syndrome

Introduction

An Inserm team at the Lille Neuroscience & Cognition laboratory (Inserm/Université de Lille, Lille University Hospital) has joined forces with its counterparts at Lausanne University Hospital (CHUV) to test the efficacy of GnRH injection therapy to improve the cognitive functions of a small group of patients with Down syndrome. First, the scientists revealed dysfunction of the GnRH neurons in an animal model of Down syndrome and its impacts on the cognitive function impairment associated with the condition. Then, seven patients conducted a pilot study testing GnRH pulsatile injection therapy. The results were promising: the therapy improved cognitive function and brain connectivity. This study has been published in Science.

Main Digest

Down syndrome, also known as trisomy 21, affects around one in 800 births and results in various clinical manifestations, including a decline in cognitive capacity. With age, 77% of people with the condition experience symptoms similar to those of Alzheimer's. Gradual loss of the ability to smell, typical of neurodegenerative diseases, is also commonly encountered from the prepubertal period, with potential sexual maturation deficits occurring in men.

GnRH Secreting Neuron Dysfunction Identified in Down Syndrome

Recent discoveries have suggested that the neurons expressing gonadotropin-releasing hormone (GnRH) - which is known for regulating reproduction via the hypothalamus - could also act on other brain regions with a potential role in other functions, such as cognition.

With this idea in mind, the Lille Neuroscience & Cognition laboratory team led by Inserm Research Director Vincent Prévot studied the mechanism which regulates GnRH in mouse models of Down syndrome.

The laboratory demonstrated that five strands of microRNA regulating this hormone's production- found on chromosome 21 - are dysfunctional. This supernumerary chromosome then leads to abnormalities in the neurons that secrete GnRH. These findings were confirmed at both genetic and cellular levels. The Inserm scientists were able to demonstrate that the progressive cognitive and olfactory deficiencies seen in the mice were closely linked to dysfunctional GnRH secretion.

Restoring GnRH Production to Restore Cognitive Function

The Inserm scientists then demonstrated that restoring physiological GnRH system function restores cognitive and olfactory functions in trisomic mice.

These findings in mice were discussed with Nelly Pitteloud, professor at the Faculty of Biology and Medicine of the University of Lausanne and head of the Endocrinology, Diabetology, and Metabolism Department at CHUV. Her research focuses on congenital GnRH deficiency, a rare disease that manifests by the absence of spontaneous puberty. These patients are given pulsatile GnRH therapy to reproduce the natural pulsatile rhythm of this hormone's secretion and induce puberty.

The researchers, therefore, decided to test the efficacy of pulsatile GnRH therapy on cognitive and olfactory deficits in trisomic mice, following a protocol identical to that used in humans. After 15 days, the team demonstrated the restoration of olfactory and cognitive functions in mice.

Pulsatile GnRH Therapy Improves Cognitive Function and Neural Connectivity in a Small Patient Group

The next stage for the scientists and doctors involved a pilot clinical trial in patients to evaluate the effects of this treatment. Seven men with Down syndrome, between 20 and 50 years of age, received one subcutaneous dose of GnRH every two hours for six months via a pump placed on the arm. Cognition and olfactory tests, as well as MRI exams, were performed before and after the treatment.

From the clinical viewpoint, cognitive performance increased in 6 of the seven patients with better three-dimensional representation, understanding of instructions, reasoning, attention, and episodic memory. However, the treatment had no impact on the ability to smell. These measures to improve cognitive functions were confirmed by brain imaging conducted by the CHUV Department of Clinical Neurosciences, which revealed a significant increase in functional connectivity.

These data suggest that the treatment acts on the brain by strengthening the communication between certain cortex regions.

"Maintaining the GnRH system appears to play a key role in brain maturation and cognitive functions," explains Prévot. "In Down syndrome, pulsatile GnRH therapy is looking promising, especially as it is an existing treatment with no significant side effects," adds Pitteloud.

These promising findings now justify the launch of a larger study - with the inclusion of women - to confirm the efficacy of this treatment in people with Down syndrome, but also for other neurodegenerative conditions such as Alzheimer's disease.

References:

GnRH Replacement Rescues Cognition in Down Syndrome

Maria Manfredi-Lozano^1,2#, Valerie Leysen^1,2#, Michela Adamo^3,4#, Isabel Paiva⁵, Renaud Rovera⁶, Jean-Michel Pignat⁷, Fatima Ezzahra Timzoura^1,2, Michael Candlish⁸,†, Sabiha Eddarkaoui¹, 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-Sempere⁹, Marc Claret¹⁰, Ariane Paoloni-Giacobino¹¹, Damien Plassard¹², Emmanuelle Paccou³, Nathalie Vionnet³, James Acierno³, Aleksandra Maleska Maceski¹³, Antoine Lutti¹⁴, Frank Pfrieger¹⁵, S. Rasika^1,2, Federico Santoni⁴, Ulrich Boehm⁸, Philippe Ciofi¹⁶, Luc Buée¹, Nasser Haddjeri⁶, Anne-Laurence Boutillier⁵, Jens Kuhle¹³, Andrea Messina^3,4, Bogdan Draganski^14,17, Paolo Giacobini^1,2, Nelly Pitteloud^3,4*, Vincent Prevot^{1,2 *}

• 1 Univ. Lille, Inserm, CHU Lille, Lille Neuroscience & 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, 1011 Lausanne, Switzerland.
• 4 Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland.
• 5 Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364, Université de Strasbourg-CNRS, Strasbourg, France.
• 6 Univ. Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron 69500, France.
• 7Department of Clinical Neurosciences, Neurorehabilitation Unit, University Hospital CHUV, Lausanne, Switzerland.
• 8 Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, 66421, Homburg, Germany.
• 9 Univ. Cordoba, IMIBC/HURS, CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain.
• 10 Neuronal Control of Metabolism Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
• 11Department of Genetic Medicine, University Hospitals of Geneva, 4 rue Gabrielle-Perret-Gentil, 1211, Genève, Switzerland.
• 12 CNRS UMR 7104, INSERM U1258, GenomEast Platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.
• 13 Neurologic Clinic and Polyclinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel; University Hospital Basel, University of Basel, Basel Switzerland.
• 14 Laboratory for Research in Neuroimaging LREN, Centre for Research in Neurosciences, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Switzerland.
• 15 Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France.
• 16 Univ. Bordeaux, Inserm, U1215, Neurocentre Magendie, Bordeaux, France.
• 17 Neurology Department, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

† New address, Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany.

# These authors contributed equally.

* These authors contributed equally.

Attribution/Source(s):

This peer reviewed publication was selected for publishing by the editors of Disabled World due to its significant relevance to the disability community. Originally authored by INSERM (Institut national de la santé et de la recherche médicale), and published on 2022/09/02 (Edit Update: 2023/01/04), the content may have been edited for style, clarity, or brevity. For further details or clarifications, INSERM (Institut national de la santé et de la recherche médicale) can be contacted at inserm.fr/en/home/. NOTE: Disabled World does not provide any warranties or endorsements related to this article.

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