Blog Section

About Huntington’s Disease and Serotonin

Serotonin (also known as 5-HT) is a neurotransmitter used to communicate important information between nerve cells. Serotonin is sometimes referred to as the “feel good” neurotransmitter owing to its association with elevated mood levels. It also has many other functions in the central nervous system including roles in sleep, depression, memory, pain, and aggression. Recent studies on mice indicate that serotonin signaling is significantly reduced in mice models of HD compared to mice without HD. Having less serotonin and the products made from serotonin may greatly impact on the progression of HD. Because the connection between HD and serotonin signaling is a fairly new development, much more investigation needs to be done before there are clear answers. Decreased serotonin may be a contributor to the development of HD or it may simply be a result of another disease mechanism. Regardless of the cause for reduced serotonin, diminished signaling in the mouse model of HD may explain some of the common behavioral symptoms associated with HD in people. (For more information about the behavioral symptoms associated with HD, click here.)

Decreased serotonin is associated with several diseases, most notably depression. Consequently, a number of drugs are already available to help bring serotonin back to normal levels in the body. The main class of drugs for this purpose is called selective serotonin reuptake inhibitors (SSRIs). Recent research has shown that, in addition to alleviating symptoms associated with HD such as depression, SSRIs may also help delay the onset of HD and prevent the degeneration of nerve cells.

Researchers have found elevated serotonin in the brains of people with HD after death, but serotonin levels in a mouse model of HD actually have decreased levels in all different age groups. However, this discrepancy does not necessarily mean that the mouse data is wrong. First of all, it is difficult to interpret human HD samples taken after death due to the large amount of nerve cell loss that occurred in life. Most of what is known about serotonin and HD in living brains comes from mouse studies because it is easier and more ethical to experiment on mice that are made to look like they have HD than it is to study humans with HD. It is important to keep this fact in mind when discussing the findings from these studies because the results from experiments on mouse models do not always translate perfectly to people with HD. Mouse studies are an imperfect but important tool in learning about HD.

One group of researchers found that, compared to non-HD mice, HD mice had only 50% of the amount of serotonin by age 12 weeks in the striatum, hippocampus, and brainstem. They also found that a related molecule derived from serotonin called 5-hydroxyindoleacetic acid (5-HIAA) is also decreased in the brain. Decreased serotonin and 5-HIAA both before and after symptoms began to appear probably indicates that the serotonin system starts malfunctioning way before the serotonin levels are decreased.

Another group of researchers tested the hypothesis that the serotonin system starts malfunctioning before it is observable with decreased serotonin. Since serotonin levels could not be used as a marker in this experiment, they tested the rate-limiting enzyme in the synthesis of serotonin, tryptophan hydroxylase (TPH). A rate-limiting enzyme is the slowest step in the creation of a molecule, and often the most important, because it requires additional energy and is highly regulated. The rate-limiting enzyme can have the biggest effect on the final product, so if something is wrong with it, the effect of this malfunction will translate down the chain to the end product. You can think of synthesis as a row of dominoes, with the goal to knock down the final domino. If one of the dominoes is missing or too small to reach the next one, the rest of the dominoes in the chain will not fall down and you will not achieve your goal. As a rate-limiting enzyme, TPH is essential to the overall production of serotonin. An alteration of TPH can therefore lead to decreased levels of serotonin in the brain overall.

Researchers have tested both the levels of TPH and its enzymatic activity. Despite normal levels of TPH, they found the activity of this enzyme was significantly diminished. This finding means that while the enzyme was present, it was not functioning properly. TPH activity was 62% less than normal before symptoms were present at 4 weeks and 86% less than normal in symptomatic 12 week old mice. These results indicate that TPH is severely damaged and account for the decreased levels of its product, serotonin.

Often, in order to compensate for decreased levels of a neurotransmitter like serotonin, the brain increases the number of receptors for that specific neurotransmitter. While this sort of “upregulation” of serotonin receptors occurs in Parkinson’s disease, it was not found to occur in the brains of HD mice. In fact, receptor binding was significantly decreased in several important areas of the brain.


We must now ask, “Why is TPH activity decreased?” The obvious answer might be that mutant huntingtin protein prevents TPH from doing its job; however, this appears unlikely. The researchers tested this hypothesis and found that the expanded polyglutamine section of the mutant huntingtin protein does not interact with TPH. Another possibility comes from the fact that TPH is very sensitive to free radical damage by reactive oxygen species. (For more information on free radical damage, click here.) It is already known that free radical damage plays a role in the progression of HD, so it is very possible that it contributes to decreased serotonin by interfering with TPH. More evidence about the role of free radicals comes from the decreased activity of TPH. Since TPH uses tryptophan to create certain products, when TPH doesn’t work, this pathway is disrupted. This disruption results in increased levels of 3-hydroxykynurenin (3HK), which makes free radicals. These free radicals can then go on to further damage TPH and many other molecules in the brain.

Now that researchers have an idea of the problem, they can begin to investigate ways to fix it. First, it must be determined whether TPH activity is also decreased in human brains, since so far it has only been tested in mice. If it is also decreased in humans, that could explain why depression is apparent before any of the motor symptoms of HD. If the current hypotheses from the mouse studies are correct, symptoms may be prevented or at least delayed by treating people at risk for HD with early antioxidants and SSRIs to keep TPH activity and serotonin levels normal. It has already been shown that one type of SSRI helped to increase TPH activity in rats.

For further reading

  1. Reynolds, et al. Brain neurotransmitter deficits in mice transgenic for the Huntington’s disease mutation. 1999. Journal of Neurochemistry 72: 1773-1776. This is a technical scientific article that discusses changes in several different neurotransmitters in the HD mouse model, including serotonin.
  2. Yohrling, et al. Inhibition of tryptophan hydroxylase activity and decreased 5-HT1Areceptor binding in a mouse model of Huntington’s disease. 2002. Journal of Neurochemistry 82: 1416-1423. This is a very technical scientific article that tested the activity of TPH, an important enzyme in the synthesis of serotonin, in a mouse model of HD.