DMS team publishes SIDS research

by Nathan Yeo | 8/1/11 10:00pm

Using research on mice with temporarily deactivated serotonin neurons, a team of researchers at Dartmouth Medical School, Harvard Medical School and the University of Iowa hope to develop tests and treatments for Sudden Infant Death Syndrome, according to DMS physiology professor Eugene Nattie.

The group's study, "Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition," was published in the latest issue of "Science" magazine on July 29. The findings of the study may eventually help research on SIDS, a syndrome marked by the unexplained death of an infant.

Studies on the brainstems of SIDS cases conducted by Hannah Kinney, a neuropathologist at Children's Hospital Boston, have indicated serotonin deficiency in the "large majority" of SIDS cases, which is central to the research on mice in Nattie's study, Nattie said.

Through a genetic transplant process, Harvard researchers inserted a receptor into the serotonin neurons of lab mice. When the mice were injected with the ligand clozapine-N-oxide, a chemical binding agent, the receptors suppressed serotonin activity in the mice for about 90 minutes, according to Nattie.

"When we just inject this ligand that the receptor responds to and we just inject it systemically then that mouse's serotonin neurons are turned off for an hour to an hour and a half," Nattie said. "So it's actually a pretty cool technique. The mouse has never had surgery. The mouse has never had anesthesia."

Introduction of the chemical allowed Nattie and other Dartmouth researchers to study the effects of reduced serotonin activity on the tested mice's behavior.

"We can test a whole variety of behaviors to see if the serotonin neurons are participating in those behaviors," Nattie said.

Mice with deactivated serotonin neurons displayed a 40 to 50-percent decrease in their ability to respond to the stress of carbon dioxide in the environment, according to Nattie. He said that both mice and humans typically breathe "deeper and faster" in response to elevated levels of CO2.

"The idea is that this is an important defense that the animal has," Nattie said. "You don't want CO2 to build up, you don't want to stop breathing. So this is one powerful mechanism that exists normally and it appears to involve serotonin neurons."

The mice also showed an inability to maintain their body temperatures without serotonin activity, according to Nattie. Warm-blooded animals such as mice and humans are normally able to maintain a constant body temperature of 37 degrees Celsius in standard room temperature, which is 24 degrees Celsius, he said.

"When we exposed these mice to the substance that turned off their serotonin neurons, and then we put them at room temperature, they could not maintain their body temperature at room temperature," Nattie said. "That's really an astounding finding because all small animals like mice and rats at room temperature are perfectly able to maintain their body temperature."

Infants who have died of SIDS are also thought to respond poorly to cold temperatures and high CO2 levels, according to Nattie.

"Our whole program project is operating under the assumption that there is a serotonin deficiency problem," Nattie said regarding SIDS. "It turns out that the exact constellation of things that are wrong in the brains of babies that have died from SIDS is very difficult to mimic in an experiment."

Nattie said that this experiment was also a scientific advancement because it involved non-fatal testing on animals.

"This experiment that was published in "Science" is really a neat way to suddenly, briskly and without any kind of invasive treatment to the animal to turn off the serotonin neurons and ask the question, Well, what happens to the animal's physiology under those circumstances?'" Nattie said. "The things that we've found are things that are reported or hypothesized to be abnormal in babies who have died from SIDS."

Nattie said he believes these initial animal tests could eventually help scientists develop not only human tests for SIDS, but also treatments.

"When you start putting the animal model into the actual world of SIDS, it becomes a little more complicated and a little bit more tenuous," he said. "The steps are, we believe, that SIDS really is a serotonin deficiency disorder, and our animal models are to try and figure out how we might tease this apart, what kind of tests we might devise that could be used to pick out infants at risk and ultimately what kind of therapy might be in play."

The study involved engineering the mice at Harvard, studying their cells at both Yale University and the University of Iowa and finally testing their behavior at Dartmouth, and was funded through a program project grant from the National Institutes of Child Health and Development, according to Nattie. The research, ongoing for about 12 years, was conducted by a team led by Kinney.

Nattie said the cooperative nature of the research and the presence of younger researchers such as Corcoran added to the effort.

"It's a very team-oriented approach, and the young people are the real drivers," he said.