ESPEYB20 5. Puberty Clinical Guidance and Studies (8 abstracts)
5.8. GnRH replacement rescues cognition in Down syndrome
Manfredi-Lozano M , Leysen V , Adamo M , Paiva I , Rovera R , Pignat JM , Timzoura FE , Candlish M , Eddarkaoui S , Malone SA , Silva MSB , Trova S , Imbernon M , Decoster L , Cotellessa L , Tena-Sempere M , Claret M , Paoloni-Giacobino A , Plassard D , Paccou E , Vionnet N , Acierno J , Maceski AM , Lutti A , Pfrieger F , Rasika S , Santoni F , Boehm U , Ciofi P , Buée L , Haddjeri N , Boutillier AL , Kuhle J , Messina A , Draganski B , Giacobini P , Pitteloud N & Prevot V
Science. 2022;377(6610):eabq4515. PMID: 36048943. https://www.science.org/doi/10.1126/science.abq4515?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Brief summary: This study identified a new role for GnRH in higher brain function using a rodent model of Down Syndrome. It reports for the first time an improvement of cognitive functions in patients with Down Syndrome treated with pulsatile GnRH.
GnRH neurons are classically described as a population of neurons located in the hypothalamus and responsible for the activation and regulation of the hypothalamic-pituitary-gonadal axis. However, the recent description of GnRH and its receptor in extrahypothalamic areas, such as the cortex and the hippocampus, has opened new avenues regarding its potential role in higher brain functions (1–3).
Patients with Down syndrome do not appear to differ from the general population in terms of puberty timing (4, 5). However, affected boys often present with gonadal insufficiency starting from infancy/puberty and being fully apparent in adulthood (4). These authors showed that the olfactory and cognitive deficits observed in a rodent model of Down syndrome (Ts65Dn mice) parallel a post-pubertal decrease in hypothalamic and extra-hypothalamic expression of GnRH. Indeed, conventional immunofluorescence and iDISCO showed a profound loss of both hypothalamic and extra-hypothalamic GnRH somata and fibers after puberty onset in Ts65Dn mice compared to controls. This was associated with an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation. Hypothalamic GnRH compensation using epigenetic, chemogenetic and pharmacological interventions abolished olfactory and cognitive defects in Ts65Dn mice. Pulsatile administration of GnRH improved cognitive function in Ts65Dn mice. Finally, pulsatile GnRH therapy in adult men with Down syndrome increased cognitive performance in 6 out of 7 cases.
This study identifies a new and unsuspected role for GnRH in cognitive function and opens new possibilities toward the therapeutic use of GnRH in people with Down syndrome. Surprisingly, pulsatile GnRH appears necessary for its role in cognitive function.
References: 1. Casoni F, Malone SA, Belle M, Luzzati F, Collier F, Allet C, Hrabovszky E, Rasika S, Prevot V, Chédotal A, Giacobini P. Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains. Development. 2016;143:3969–3981. 2. Skrapits K, Sárvári M, Farkas I, Göcz B, Takács S, Rumpler É, Váczi V, Vastagh C, Rácz G, Matolcsy A, Solymosi N, Póliska S, Tóth B, Erdélyi F, Szabó G, Culler MD, Allet C, Cotellessa L, Prévot V, Giacobini P, Hrabovszky E. The cryptic gonadotropin-releasing hormone neuronal system of human basal ganglia. Elife. 2021;10:e67714. 3. Schang AL, Ngô-Muller V, Bleux C, Granger A, Chenut MC, Loudes C, Magre S, Counis R, Cohen-Tannoudji J, Laverrière JN. GnRH receptor gene expression in the developing rat hippocampus: transcriptional regulation and potential roles in neuronal plasticity. Endocrinology. 2011;152:568–580. 4. Hsiang YH, Berkovitz GD, Bland GL, Migeon CJ, Warren AC. Gonadal function in patients with Down syndrome. Am J Med Genet. 1987;27(2):449–458. 5. Erdoğan F, Güven A. Is there a secular trend regarding puberty in children with down syndrome? Front Endocrinol (Lausanne). 2022;13:1001985.
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ESPE Yearbook of Paediatric Endocrinology
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