GnRH replacement rescues cognition in Down syndrome

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. Description Intervention for Down syndrome Down syndrome (DS), the result of trisomy of chromosome 21, carries a suite of symptoms including intellectual disability and loss of olfaction. Manfredi-Lozano et al. recognized a similarity between some of the DS symptoms and those seen in patients with a deficiency of gonadotropin-releasing hormone (GnRH) (see the Perspective by Hoffmann). Indeed, analysis of a mouse model of DS showed deficits in GnRH expression. Interventions that restored physiological GnRH levels in the mouse DS model also improved cognitive deficits. In a preliminary clinical trial in patients affected by DS, pulsatile GnRH therapy improved cognition. —PJH In a mouse model and in patients, cognitive symptoms of Down syndrome respond to restoration of gonadotropin-releasing hormone. INTRODUCTION Patients with Down syndrome (DS), a frequent condition (1 per 800 live births) caused by trisomy of chromosome 21, display a variety of characteristics, including cognitive decline due to an early-onset Alzheimer-like disease along with myelination defects in adulthood, impaired olfaction starting before puberty, and subfertility. No viable treatment exists for the cognitive and olfactory deficits seen in DS patients. RATIONALE Gonadotropin-releasing hormone (GnRH), which is secreted in a pulsatile fashion by specialized hypothalamic neurons, is the master molecule that controls reproduction in all mammals. In humans, altered GnRH secretion leads to Kallmann syndrome, which manifests with olfactory defects, gonadal immaturity, and infertility. Hypothalamic GnRH-expressing neurons also project to extrahypothalamic areas, including those involved in intellectual functions. We therefore asked whether the progressive deficits observed in DS bore any temporal correlation to the maturation of the GnRH system; what alterations to this process, if any, could be observed in the brain of animal models of DS; and whether these alterations could be therapeutically reversed in adulthood. RESULTS We first further characterized a trisomic mouse model of DS that triplicates regions analogous to human chromosome 21 (Ts65Dn mice) and displays subfertility and progressive cognitive and olfactory impairments similar to that of DS patients. These nonreproductive neurological symptoms closely paralleled a postpubertal loss of GnRH neurons and fibers in the hypothalamus as well as in extrahypothalamic regions, which is reflected by changes in the levels and pattern of release of the gonadotropin luteinizing hormone (LH) in the blood. The decreased GnRH expression in adult mice was accompanied by an imbalance in a complex network of microRNAs (several of which occur on the trisomic region) and regulatory factors that constitute a “switch” that controls GnRH expression and GnRH neuron maturation in the hypothalamus, starting during the infantile period or “minipuberty.” Indeed, we observed that elements of this switch were dysregulated as far back as the minipubertal period, well before the appearance of cognitive or olfactory deficits. Additionally, this altered expression of microRNAs and transcription factors in the hypothalamus appeared to result in the altered expression of a number of target genes, including several involved in myelination and synaptic transmission, both in the hypothalamus itself and, to a much greater extent, in the hippocampus, as well as in the altered activity of hippocampal neurons. Overexpressing a key microRNA involved in the GnRH developmental switch, miR-200b, in the hypothalamus abolished both the changes in gene expression and the deficits in neuronal activity, olfaction, and cognition in DS mice. Reinduction of miR-200b in adulthood, long after the GnRH switch, increased both the number of GnRH-expressing neurons in the hypothalamus and the proportion of neurons expressing one of its transcriptional activators, Otx2, which is known to control the opening and closing of other critical periods in brain maturation. To verify that these improvements were indeed due to the restoration of GnRH, we used cell therapy with normal hypothalamic neurons as well as chemogenetic and pharmacological interventions to produce GnRH at physiological levels and patterns (i.e., pulsatile secretion) in adult DS mice and found that these treatments all abolished olfactory and cognitive defects in the mice. Finally, based on these results, we performed a pilot study in DS patients to assess the effects of pulsatile GnRH therapy on olfaction, cognition, and brain structure and function. This treatment is safe and is presently used to treat GnRH-deficient conditions like Kallmann syndrome. We found that a 6-month pulsatile GnRH treatment improved both cognitive performance and functional brain connectivity in these patients. CONCLUSION The maintenance of the GnRH system appears to play a developmental role in brain maturation and higher functions. Pulsatile GnRH therapy holds promise to improve cognitive deficits in DS, paving the way for future clinical trials. Pulsatile GnRH therapy improves cognition in DS. DS patients show olfactory and cognitive impairments in addition to intellectual disability and reproductive maturation deficits. GnRH neurons, which control reproduction, also project to brain areas involved in cognition such as the hippocampus. In trisomic Ts65Dn mice, which mimic characteristics of DS patients, GnRH expression progressively disappears. Pulsatile GnRH therapy in DS patients improves brain connectivity and function. IU/liter, international units per liter.

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