A Role for the Endocannabinoid System in Down Syndrome

Scientists out of Spain led by Dr. Andrés Ozaita revealed last month in their publication in the journal Neurology of Disease that the endocannabinoid system (ECS) may be involved in the pathogenesis of Down syndrome (DS). Their study was the first to implicate the ECS as a possible contributing cause to the cognitive deficits seen in people with DS. The ECS is a biological system made up of receptors, ligands, and enzymes responsible for making and destroying endocannabinoids. It runs throughout the body and is the target of the phytocannabinoids THC and CBD, as well as others.

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DS is the most common genetic cause of mental disability. It is caused by the total or partial trisomy of chromosome 21 and affects one in every 700-1000 live births. It is most commonly associated with anatomical abnormalities and intellectual disability. However, people with DS are more likely than non-DS people to develop other diseases such as congenital heart defects, leukemia, Alzheimer's disease, and Hirschsprung disease, to name a few. Thus Dr. Ozaita's team's findings may point to a potential therapeutical target for DS patients.

The authors used two reliable mouse models of DS, the segmentally trisomic Ts65Dn model and a transgenic mouse model overexpressing a single gene candidate for DS cognitive phenotypes. With these two models, the researchers used pharmacological methods to decrease the activity of the cannabinoid receptor type 1 (CB1). First, the team found that in the hippocampus, in which DS patients show marked deficits in hippocampal-dependent memory, there is an overexpression of CB1 receptors in their model mice. Even more, this overexpression is limited to excitatory neurons over inhibitory ones. This could change the excitability/inhibition balance of activity in the region. To investigate if this had any consequence on the normal functioning of the hippocampus, they administered the CB1 antagonists rimonabant or a compound called NESS 0327 for seven days.

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After the mice underwent this injection schedule they showed marked improvement in hippocampal-dependent memory tests. Not only that, but the researchers were able to restore synaptic plasticity, and, most interestingly, rescued hippocampal neurogenesis. Neurons within the hippocampus are able to be produced throughout the lifespan and are thought to be very important in memory.

The exact cause for these alterations has remained unknown. The authors of the present research decided to target the ECS because it is very involved in "fine-tuning" these very same processes. Endocannabinoids have been recognized for their role as neuromodulators and in physiological homeostasis. That is, they make sure several bodily processes are in check. If this modulation is out of sorts in the hippocampus in patients with PD, it could explain some of their learning and memory problems.

As far as the authors know, there are no pharmaceutical treatments available to help improve the intellectual capabilities in DS patients, although some pharmacological treatments have been tried (see here for a review). Targeting the CB1 receptor may be a viable treatment to improve DS patient's quality life. Nevertheless, the disease is genetic, and thus we must wait for accessible genetic therapy specifically designed to treat chromosomal mutations. Yet, regardless of treatment choices, we must remember to give those with DS the opportunity to participate in society and grant them the respect that every individual deserves.    

Sources: Neurology of Disease, Handbook of Experimental Pharmacology, Progress in the Chemistry of Organic Natural Products, ScienceDaily.com, Journal of Biomedical Science , Disease Models and Mechanisms, ACS Chemical Neuroscience, Cell Metabolism, Drug Design, Development and Therapy