Friday, October 3, 2008

Study suggests serotonin plays a role in SIDS

Archive for Saturday, July 05, 2008
Study suggests serotonin plays a role in SIDS

Mice who overproduced the brain chemical showed symptoms similar to those of the infant syndrome before they died.

By Wendy Hansen
July 05, 2008

Mice genetically engineered to overproduce the brain chemical serotonin died at an early age after developing symptoms similar to those of sudden infant death syndrome, suggesting improper regulation of serotonin may cause SIDS in humans.

The majority of the mice died after being unable to regulate their heart rate and body temperature, scientists reported Friday in the journal Science.

Dr. Cornelius Gross, a study author and head of the project at the European Molecular Biology Laboratory in Monterotondo, Italy, said the work might prompt clinical research "to devise diagnostic tests to try to identify those kids most likely to . die of SIDS."

SIDS is a condition in which seemingly healthy babies between 1 month and 1 year old die without warning or explanation. It kills approximately 2,700 infants in the U.S. each year.

The mice were part of a study on serotonin's role in aggression and anxiety, but after they began dying, a scientist suggested the deaths might be related to SIDS.

"This was a chance discovery," Gross said.

Serotonin, in addition to affecting mood, regulates bodily functions such as temperature, respiration and heart rate.

The findings support autopsy-based results reported from 2006 in which researchers from Children's Hospital Boston, led by Dr. Hannah Kinney, found that infants who died of SIDS had abnormal serotonin-producing cells in their brain stems.

Although differences exist between the mice and babies who die of SIDS, both reports point to improper regulation of the serotonin system as a cause of the disorder, the researchers said.

"The main impact is if you produce a very specific deficit in the serotonin system, you get a disastrous result," said Dr. Gene Nattie, a professor of physiology at Dartmouth Medical School, who worked with Kinney. "That's why the paper is important. It's certainly a big step forward."

SIDS-like symptoms in mice with serotonin signaling defects
By John Timmer | Published: July 03, 2008 - 12:59PM CT

Sudden Infant Death Syndrome, or SIDS, is an extremely challenging thing to study. For years, it wasn't even clear whether the deaths of infants with no apparent abnormalities represented a distinct biological phenomenon. Over time, however, monitoring of infants revealed unexplained lapses in their regulation of body temperature and heart rate, and postmortem examinations suggested an association with defective signaling involving the neurotransmitter serotonin. Now, researchers exploring serotonin signaling in mice may have created the first animal model of SIDS; a description will appear in today's issue of Science.

It's not at all clear that SIDS was what the group were after, since serotonin is involved in a wide variety of neural process, and its signaling pathway is the focus of a lot of drug development. Still, if chance favors the prepared mind, the researchers appear to have been very well prepared.

Their work focused on creating a mouse strain where the activity of the serotonin pathway could be manipulated experimentally. To do so, they used the Htr1a receptor, which helps tone down serotonin signaling. When this receptor binds the neurotransmitter, it actually inhibits the function of other receptors, producing a net decrease in serotonin signaling. The authors placed the Htr1a gene under the control of regulatory proteins such that it would normally be expressed, but administration of a drug called tetracycline would shut the gene down; for the purposes of this discussion we'll call that genetic construct Tet-Htr1a.

Mice that completely lack the Htr1a gene are fully viable, and those with the Tet-Htr1a combination were born in the expected number. But the majority of the mice died during the first few months after birth; by four months, roughly 70 percent of them were dead. Mortality rates returned to normal after this point, and the death could be completely suppressed by the administration of tetracycline, linking it directly to the gene.

The researchers started monitoring the mice, and found what they termed "sporadic autonomic crises" occurred in most of the Tet-Htr1a animals. These involved several hours in which body temperature was dysregulated, producing hypothermia; these periods also saw incidents of severe bradycardia. About 40 percent of the time, the mice did not recover, and died.

The authors argue that this provides a useful model of human SIDS, as serotonin signaling influences the function of the autonomic nervous system, which controls the activity of things like breath and heart rate. Serotonin signaling is also active during changes between sleep and wake states, which may explain the frequency of SIDS events associated with sleep. They do, however, recognize that the parallels are not exact; the mice involved are actually sexually mature during the time the deaths occur. Still, it's far better than not having a way to study the phenomenon at all.

Science, 2008. DOI: 10.1126/science.1157871

Science: Leading Cause of Infant Death Explained by Serotonin Receptor

New research in Science provides a specific biological mechanism for Sudden Infant Death Syndrome (SIDS), providing new insight into a lethal and unpredictable affliction that claims the lives of about 2500 seemingly healthy infants every year in the United States.

Until now, biological risk factors have been difficult to pinpoint. Dysfunction of the brain transmitter serotonin was believed to trigger SIDS, but no one really knew how. A report in the 5 July issue of Science shows that a particular serotonin receptor creates faulty serotonin signaling and is enough to cause death in a mouse model of SIDS.

Risk factors for SIDS include sleeping stomach-down and overheating during sleep.

Low serotonin has been long been suspected as a risk factor but no mechanism for the deficiency had ever been identified. Enrica Audero-a postdoctoral fellow at the European Molecular Biology Laboratory in Monterotondo, Italy-and her colleagues investigated how over-expression of a serotonin receptor triggered serotonin dysfunction and frequently led to death in mice.

The researchers focused on the serotonin 1a receptor, a protein on nerve cells that works with serotonin to send chemical messages. Serotonin 1a receptors are autoreceptors-they can turn off serotonin if too much is released, much as how a thermostat senses and responds to temperature. Nerve cells that produce serotonin are clustered in the brainstem, which regulates basic body functions including heart rate and breathing.

Other studies have found that activating serotonin 1a receptors leads to less firing of serotonin-containing nerve cells and decreases in heart rate, body temperature and respiration-which are also physiological factors contributing to SIDS.

Audero and her colleagues engineered transgenic mice with about 10 times more serotonin 1a receptor protein compared to their healthy, control littermates. When spritzed with tryptophan-a precursor for serotonin-brain slices from mice with serotonin1a receptor over-expression showed less cell-firing than control mice. The plunge in firing rate was evident within a few minutes of applying tryptophan; it was as if over-expressing serotonin 1a receptors led to an exaggerated shut-off of cells containing serotonin. If the researchers added a drug that blocked the serotonin 1a receptor, tryptophan was able to restore cell-firing. The finding demonstrates that the serotonin 1a receptor was causing the serotonin shut-off.

The researchers were simply looking for how serotonin feeds back on itself, when they began to realize that their engineered mice could be a model for SIDS.

"The majority of mice died suddenly early in their life," Cornelius Gross, senior author on the Science paper and researcher at the European Molecular Biology Laboratory, said during a AAAS/Science teleconference. Gross said the deaths were surprising because mice with genetic modifications to other parts of the serotonin signaling pathway do not die. The researchers looked at what was happening to the serotonin 1a over-expressing animals just before death, and they found a "dramatic drop" in heart rate and body temperature, Gross said.

At least one drop in heart rate and body temperature-called "sporadic autonomic crisis"-occurred in 73% of the serotonin 1a over-expressing mice. It took these animals hours and sometimes days to recover. In 37% of the transgenic mice, the crisis was so severe that the animals died.

"The events that precipitated crises in our animals are not known, and thus far we have not been able to identify environmental stressors that induce crises," wrote Audero and colleagues in Science. "However, we speculate that crises may occur preferentially after rapid changes in serotonin neuron activity." Such activities could occur during sleep-wake cycles.

The authors caution that their results may not directly explain SIDS, because SIDS infants do not show greater serotonin 1a receptors. But, it is possible that other "functionally equivalent deficits" in serotonin signaling may be at play.

Because the findings suggest that SIDS arises from abnormal brain development, the study could provide comfort to parents of babies who have died from SIDS. "I think it says to parents that their babies had a developmental disorder that they were born with," Marian Willinger, SIDS expert at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, said during a AAAS/Science teleconference on 3 July. SIDS babies are typically found dead in their cribs in the morning, frequently leading parents to blame themselves.

Willinger said that having an infant die of SIDS is a "devastating event" for a family. The Science study "should provide them with some sense of comfort that there was nothing they could have done to prevent it-it is a real disease," she said.

Brandon Bryn and Molly McElroy
3 July 2008