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 Auderoˇa 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 respirationˇwhich 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.
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 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 itˇit is a real disease," she said.
Brandon Bryn and Molly McElroy