By David N. Leff

Sudden Infant Death Syndrome - SIDS - is the target of much research but little understanding. We don't hear anything about what might be called "Sudden Adult Death Syndrome," which usually is diagnosed as a fatal heart attack.

Neuroscientist Chi-Sang Poon, a principal investigator at the Harvard-MIT Division of Health Sciences and Technology in Boston, cautiously suggests a link between the two lethal occurrences: "Anybody - not just babies - who suffers from respiratory depression," Poon observed, "is potentially at risk of respiratory failure and sudden death."

Unlike reading, writing and remembering, you needn't make a conscious effort to inhale and exhale. Breathing is an automatic function of the body, governed by nerves and synapses in the brain stem. Neuroanatomists describe this component of the human brain as the "lower" brain. This refers not only to the brain stem's position south of the more prominent cerebral cortex, but to its thoughtless activities, in contradistinction to the "higher" brain functions of that cortex - such as learning, memory and cognition.

That piece of cerebral snobbery may be in for a bit of comeuppance, thanks to a serendipitous discovery by Poon, reported in the May 1, 2000, issue of the twice-monthly Journal of Neuroscience. Its title: "NMDA receptor activity in utero averts respiratory depression and anomalous long-term depression in newborn mice."

"That discovery," Poon told BioWorld Today, "was a somewhat accidental observation because our original explicit purpose in creating these mice with their NMDA receptors knocked out was for studying learning and memory in the hippocampus. But then in that first generation of animals, the NMDA receptors were knocked out throughout the entire brain. So it affected multiple sites, including the brain stem area. And all of a sudden these KO mice became not viable."

Mice Missing Receptor Barely Breathe, Suckle

"They suffered from some phenotypic abnormalities," Poon recounted, "the most significant of which is that they could not breathe normally. In fact, all of the animals turned bluish within 20 hours or so of birth, and died of respiratory failure. There were other complications, too, of course," Poon went on. "They could not suckle well, so they were somewhat malnourished."

This seemed a far cry from the hippocampal cognitive effects that Poon and his co-authors were looking for, so they removed brain tissues from their mutant mice and put them under the microscope. "Because they couldn't breathe," Poon recounted, "we tried to look at the areas of the brain that are critical for cardiorespiratory regulation. And we focused on an area of the brain stem called the nucleus tractus solitarium, which is a sort of gateway for a lot of inflowing visceral and cardiopulmonary nerve bundles.

"We studied neurotransmission in this area and discovered that it exhibited a very profound long-term depression, or LTD. Long-term depression," Poon explained, "refers to the depression of synaptic transmission between neurons. This is generally believed to be one form of memory system as well. People have been trying to figure out what causes us to learn and remember new things. The prevalent hypothesis these days is that synapses in the brain change over time after repeated use. And these changes, either up- or down-regulation - LTD (depression) or LTP (potentiation) - could be long-lasting after episodes of learning. So LTD and LTP represent one form of learning, so to speak.

"Learning and memory are generally believed to be cognitive functions," Poon continued, "mostly expressed in a higher-level brain area - the hippocampus, cortex and cerebellum. What we have found, and now confirmed by these mutant-mouse studies, is that learning and memory could also occur at a subconscious level in the lower-level brain stem's activities. We normally do not have the ability to control it," he pointed out, "as these are activities happening at a subconscious level."

In the hippocampus, a key neurotransmitter, the NMDA (N-methyl-D-aspartate) receptor, honchos the neurons that handle learning and memory. It was this receptor that the co-authors disabled in their mutant mice - in the brain stem as well as the hippocampus, it turned out.

"The two are responsible for very different functions, of course," Poon observed. "The higher, conscious hippocampus is believed to be responsible for temporary, short-term memory - a cognitive transient relay station for remembering things kept for the long term. Now what we are trying to say is that in the brain stem - even though we are not conscious about it - there is actually a lot of so-called cognition going on.

"We don't pay much attention to the subconscious brain-stem area," he pointed out, "because things there are happening independently of our control. The point is that there are just about as many exciting things going on as in the higher brain centers, although we are not conscious of them. The brain stem can learn and remember if you accept the thesis that LTD and LTP are the kernels of learning and memory."

Poon made the practical point that "the NMDA receptor plays a very important role in the development of brain-stem areas responsible for vital functions in newborn mammals. This happens prenatally, too," he added, "so if pregnant women are exposed to drugs of abuse - such as angel dust, ketamine, alcohol - they could potentially put their babies at risk after birth."

Risk Factors Of Pregnancy, Prematurity, SIDS

"There's another important clinical implication," he pointed out, "for babies born prematurely. We know now that NMDA receptors are expressed very late during pregnancy. Babies born prematurely could be at risk of maldevelopment, because if the birth occurred before the critical period for normal development in the brain, for normal cardiorespiratory function, then these preemies would be at risk of cardiorespiratory abnormality. Their breathing becomes irregular, and sometimes they cease breathing altogether. These infants often have suckling difficulties also. Usually they will grow out of those problems after a while. So that's an indication of how brain development could affect their well-being."

Poon surmises that similar factors may be present in SIDS - sudden infant death syndrome. One of these SIDS risk factors," he suggested, "should be respiratory depression. So conceptually SIDS babies may have been born with defective NMDA receptors.

"At this stage of the game," Poon concluded, "SIDS is so widespread, but so unclear, that any factors that could lead to some clues would be very useful."

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