There is a hypothesis, in principle plausible until proven otherwise: the possible positive action of the GnRH system on cognition (in addition to the known endocrine actions). The study aims to confirm this hypothesis and, at the same time, to demonstrate the benefit it could bring to the manifestations of cognitive impairment in people with Down's syndrome. 

The preclinical study focuses on the Ts65Dn mouse, one of several murine models of Down's syndrome. It has been the most widely used so far, but is far from the perfect model (Klein JA and Haydar TF (2022) and Drug Therapy: Neurodevelopment and Neurodegeneration in Down Syndrome). 

The studies carried out by the authors in this model with regard to the development of the GnRH system are complex and demonstrative in their various aspects. I consider the experimentation on cognition in the mouse to be somewhat weak. 

There are dozens of products already tested in the Ts65Dn mouse which, having sometimes substantially improved brain function and cognitive tests in this model, have subsequently failed when the experimentation was transferred to people with Down's syndrome. Hence the need to always test in other models. 

The clinical trial is very tentative and lacks the conditions required to show positive effects objectively. It should have been double-blind and compared with placebo, and with a larger number of subjects. I am surprised that Science has accepted that part of the work. 

In this study, the authors show that, with age, there is a loss of neurons that synthesise gonadotropin-releasing hormone (GnRH) in a mouse model of Down's syndrome, which the authors relate to the loss of cognitive capacity.  

GnRH plays a major role in the control of reproductive function, but its receptor is also expressed in the hippocampus, a key brain area responsible for cognition affected by ageing and impaired in Down's syndrome where, however, its function is not well defined.  

The authors convincingly show the involvement of GnRH in the function of brain regions related to learning and memory such as the hippocampus. By correcting for GnRH depletion in trisomic mice, the authors rescued functional deficits in plasticity and learning and memory in the hippocampus. Given the positive results in mice, they also tested pulsatile GnRH administration in a small group (only seven individuals) with Down syndrome, in which they obtained a moderate improvement in some cognitive tests and detected, through functional neuroimaging studies, an increase in functional connectivity in some brain regions.  

While certainly interesting and promising, I would be cautious in anticipating developments, because more clinical trials are needed to demonstrate real clinical efficacy. At the moment there are quite a number of clinical trials underway to improve cognition in people with Down syndrome, some of which gave good results when tested in a small number of individuals, but then failed when the number of participants was increased. 

There has been extensive evidence for years of a link between gonadotrophins and age-related cognitive decline, and also Alzheimer's disease, and recent work shows that GnRH analogues may have important anti-inflammatory effects, which could be beneficial in both Alzheimer's disease and Down's syndrome. In fact, there is already a clinical trial in women with mild-moderate Alzheimer's disease using a GnRH agonist that demonstrated efficacy in a Phase II clinical trial in women with Alzheimer's disease who also received the acetylcholinesterase inhibitor donepezil. 

The experiments in mice are elegant and support the authors' hypotheses. Possibly the weakest part is the clinical study, in which the authors only tested seven people with Down's syndrome. Therefore, while certainly interesting and promising, we should be careful not to raise too many expectations among families. In addition, one caveat is that while the authors also see deficiencies in female mice, they did not include females in their clinical study. 

Many previous studies have identified the molecular mechanisms of hippocampal deficits in Down's syndrome, and some have also yielded positive results in clinical studies. However, Down syndrome research has mainly focused on protein-coding genes, whereas we now know that there are other genomic regulatory elements that may also play a role in brain disorders. 

The most interesting finding, in my view, is the imbalance found in a complex network of microRNAs, which the authors previously reported regulates GnRH expression and the maturation of GnRH neurons. MicroRNAs are a class of RNAs that play important roles in regulating gene expression, and several of them are encoded by chromosome 21. Therefore, this work suggests that regulatory elements, such as microRNAs, may play a mechanistic role in the neuropathology of Down syndrome.