Sudden infant death syndrome and serotonin:
Dartmouth Medical School, Lebanon, NH, USA
The sudden infant death syndrome (SIDS) is the sudden,
unexpected death of an infant that is not explained by
autopsy, death scene examination, and history. The
etiology is unknown. Recent postmortem studies have
discovered abnormalities in brainstem serotonergic neu-
rons, but how these translate into dysfunction and cause
SIDS is uncertain. Recently, lethal effects in transgenic
mice with overexpression of the serotonin 1A autorecep-
tor have been described. Many die spontaneously
between postnatal day 40 (P40) and P80, and some
spontaneously exhibit bradycardias and drops in body
temperature. The severity of the autonomic dysfunction
and its age dependence suggest relevance to SIDS.
However, SIDS cases have decreased serotonin 1A auto-
in the mice, and the peak incidence of SIDS is between 2
and 6 months of age, which is arguably younger (in
relative terms) than the ages at which the mice die.
Nevertheless, the description of an animal model with
serotonin defects that has autonomic dysfunction and
spontaneous mortality at a young age is an exciting
finding of possible importance for understanding SIDS.
Keywords: 5-HT; brainstem; SIDS
SIDS is the sudden, unexpected death of an infant that is not
explained by autopsy, death scene examination, and
history.(1)Overall there are currently ?2000 SIDS deaths
per year intheUS andall motherscertainly worryaboutSIDS.
There are many theories to explain SIDS, but recent work has
focused attentionon serotonergic neurons inthe brainstem.(2)
Postmortem examination of brains from SIDS cases has
revealed, in a majority of cases, a triad of serotonergic
abnormalities(2)including (i) increased number of serotonin
neurons many of which appear immature, (ii) decreased
binding of the serotonin 1A autoreceptor, and (iii) decreased
relative serotonin transporter binding. Further, four genetic
studies have shown a higher incidence in SIDScases of the L/
L genotype and/or the long (L) allele in the promotor region for
the serotonin transporter gene,(3–6)
although a similar
examination of the coding region for the serotonin 1A
autoreceptor did not demonstrate any link with SIDS.(7)
These data point to serotonin abnormalities in many SIDS
cases, but are difficult to interpret in any mechanistic way.
Does SIDS have a genetic origin? Or is it the result of an
environmental stress? Or both? Are the serotonergic
abnormalities a primary event or an epiphenomenon? How
might the serotonergic abnormalities result in physiological
dysfunction that contributes to SIDS?.
Triple risk hypothesis
The triple risk hypothesis has proven useful in thinking about
SIDS causation.(8)It posits that SIDS results from the
unfortunate coincidence of (i) an infant with specific under-
homeostatic stressor at the time of death. The serotonin
abnormalities could contribute to the underlying vulnerability.
SIDS would then require a stressor that occurs at the critical
period, which is between 2 and 6 months of age..
Animal models that alter function of serotonin neurons during
early postnatal life are useful in understanding how the
serotonergic system affects autonomic and respiratory
control processes that could contribute to sudden death.
They provide insight into possible mechanisms for SIDS.
These have taken two generic forms: pharmacological
manipulation in early postnatal life; and alteration of a single
gene function from inception. In the first, the dysfunction
begins in early postnatal life; in the second it is present from
early prenatal life.
Loss or inhibition of serotonergic
Studieswith lesions of serotonergic neurons in the medulla by
early postnatal injection of toxins via the cisterna magna in
newborn piglets have shown that the ventilatory response to
increased CO2is reduced in males during sleep (there is a
male predominance in the incidence of SIDS).(9)Focal acute
What the papers sayDOI 10.1002/bies.200800200
*Correspondence to: E. Nattie, Borwell Bldg, Dartmouth Medical School,
Lebanon, NH 03756-0001, USA
BioEssays 31:130–133, ? 2009 WILEYPeriodicals,Inc.