Cot death and serotonin

Behind the Headlines

Friday July 4 2008

Babies should always be laid to sleep on their back

“The key to cot death may be a brain-signalling chemical that is better known for regulating mood,” The Times reported. It said that experiments in mice had suggested that an imbalance of serotonin in the brainstem could be involved in sudden infant death syndrome (SIDS). It continued that the study could have identified a possible genetic cause, but environmental factors, such as parental smoking, may also play a part in raising risk. The Daily Telegraph suggested the research could one day lead to the availability of screening to identify high-risk babies for extra monitoring and care.

This well-conducted laboratory study found that mice which overproduce a regulator of serotonin (leading to reduced serotonin activity) are less able to control heart rate and breathing and have sporadic crises that can lead to death. There appeared to be a critical period in the mice’s early life when they were more susceptible to these effects. At present, the human application of these findings is not clear. Screening for SIDS is unlikely to be available in the immediate future. This development of a ‘mouse model’ for the syndrome can be used to further understand the complex metabolic and autonomic processes that underpin SIDS.

Where did the story come from?

Dr Enrica Audero and colleagues from the European Molecular Biology Laboratory and the Laboratory of Behavioural Neuropharmacology in Italy carried out the research. The study was published in the peer-reviewed medical journal: Science.

What kind of scientific study was this?

This laboratory study in mice was set up to better understand the role of serotonin in the brain. Serotonin is a chemical messenger that plays a role in emotions such as anger, aggression and mood. Its activity starts in the brain stem, at the base of the brain in a region known as the ‘raphe nucleus’. From here serotonin neurons connect to all parts of the central nervous system and carry messages along nerves. Postmortem examinations have revealed that babies who die from sudden infant death syndrome (SIDS) have deficits in serotonin neurons in the raphe area of the brain.

In this study, the researchers bred genetically modified mice that produced an excess of a particular protein in their brains - Htr1a. This protein is a receptor for serotonin, and when activated leads to a reduction in the activity of serotonin and a consequent reduction in heart rate, body temperature and respiration. The researchers determined how the over-production of this protein in the brain affected the lifespan of the mice. They also investigated if the drug doxycycline (which can reverse the effects of Htr1a) would affect their survival. The researchers were also interested in the timing of the over-expression of the protein (i.e. if its over-production resulted in higher death rates in young mice).

By monitoring the mice’s heart rate, body temperature and movement, the researchers assessed the physical effects of the over-expression of Htr1a (i.e. the repression of serotonin activity). They also studied slices from the mice’s brains to see how serotonin was affected by an abundance of this protein.

In another set of experiments, the researchers investigated the downstream effects of the repression of serotonin. The response of mice with an excess of Htr1a (i.e. they had deficits in serotonin) was compared with that of normal mice when both types were exposed to cold temperatures (4°C) for 30 minutes.

What were the results of the study?

To reduce the risk of SIDS, the following precautions can be taken;

  • Babies should always be laid to sleep on their back
  • Blankets should be tucked in and arranged to avoid accidental suffocation
  • Do not expose babies to tobacco smoke as this can dramatically increase risk of SIDS
  • The best place for babies to sleep in the first six months is in a crib or cot. They should never be brought into their parent’s bed or left to sleep alone in an adult bed. Falling asleep on the sofa with a baby increases risk
  • Keep the baby's room at a safe and comfortable temperature and don’t give them too many blankets or clothing. The baby's room should ideally be 18C (64F) but needs to be between 16-20C (61-68F)

There are several relevant findings from this complex study. To begin with, the researchers confirmed that the genetically engineered mice had an over expression of the Htr1a receptor, and this resulted in reduced serotonin neurotransmission. The majority of mice with an increased concentration of Htr1a protein died before reaching three months. This death could be prevented by treating the mice continuously with doxycycline (which reverses the effects of the protein).

Furthermore, the researchers found that the genetically modified mice were more likely to die if over expression of the protein began during an earlier developmental phase. The researchers noted that 73% of the mutant mice had at least one ‘crisis’ in which their heart rate and body temperature decreased inexplicably. These crises sometimes persisted for days, and in a number of cases led to death. There were no such crises observed in the normal mice.

As a result of the over-expression of the protein, the modified mice’s nervous responses were also affected, and those that were exposed to cold failed to activate a process which leads to body warming.

What interpretations did the researchers draw from these results?

The researchers concluded that their findings link “sporadic autonomic crisis and sudden death”. They say that their mouse model may help in the further understanding of the diagnosis and prevention of SIDS.

What does the NHS Knowledge Service make of this study?

This is a well-conducted study in mice that used recognised methods to explore complex biochemical pathways, and their effects on the body and on survival. As it went some way to developing a ‘mouse model’ for an important human syndrome, it will be of particular interest to the scientific community. The following points are important:

  • The main finding of this study is that increased expression of the Htr1a receptor reduces the activity of serotonin neurones, leading to sporadic autonomic crises and sometimes death. Importantly, the researchers acknowledged that it appeared that SIDS infants “do not exhibit increased Htr1a autoreceptor expression”. However, they said it is possible that human babies may have equivalent deficits that lead to changes in important biochemical pathways.
  • The researchers also acknowledged that certain features of SIDS in humans are not reflected in their mouse model, namely the gender difference (male babies are more susceptible) and particular characteristics of the way Htr1a acts. Metabolism in mice is obviously different to that in humans. Whether this model can be directly applied to the human situation remains to be seen.

The implications of these findings for the human situation are currently not clear. Improved diagnoses, prevention or screening for SIDS as a result of this research is a long way off.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Cot death risk 'higher for babies with imbalance of mood chemical'. The Times, July 4 2008

Cot death risk test to come from brain chemical find. The Daily Telegraph, July 4 2008

Links to the science

Audero E, Copp Ei, Mlinar B, et al. Sporadic Autonomic Dysregulation and Death Associated with Excessive Serotonin Autoinhibition. Science 2008; 321:130–133


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