Sudden infant death syndrome and serotonin: Animal models

Dartmouth Medical School, Lebanon, NH 03756-0001, USA.
BioEssays (Impact Factor: 4.73). 02/2009; 31(2):130-3. DOI: 10.1002/bies.200800200
Source: PubMed


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 neurons, but how these translate into dysfunction and cause SIDS is uncertain. Recently, lethal effects in transgenic mice with overexpression of the serotonin 1A autoreceptor 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 autoreceptor binding, which is opposite to its overexpression 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.

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    • "Limited physiologic data in infants show episodes of apnea and bradycardia before a SIDS death (Meny et al., 1994; Poets et al., 1999), consistent with the longstanding hypothesis that SIDS is related to a brainstem abnormality in the neuroregulation of cardiorespiratory control (Hunt and Brouillette, 1987). It is not yet known whether the anatomical defects identified in SIDS cases are associated with an increase or a decrease in function of the 5-HT system (Paterson et al., 2006; Kinney et al., 2008), but better defining the roles for 5-HT neurons in control of breathing during development using transgenic animal models (Erickson et al., 2007; Audero et al., 2008; Alenina et al., 2009; Nattie, 2009) may provide insight into how 5-HT neuron defects could lead to pathophysiological changes that cause SIDS. "
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    ABSTRACT: Central serotonin (5-HT) neurons modulate many vital brain functions, including respiratory control. Whether breathing depends critically on 5-HT neurons, or whether their influence is excitatory or inhibitory, remains controversial. Here we show that neonatal Lmx1b(flox/flox;ePet-Cre/+) mice (also called Lmx1b(f/f/p) mice), which selectively lack serotonin neurons, display frequent and severe apnea lasting as long as 55 s. This was associated with a marked decrease in ventilation to less than one-half of normal. These respiratory abnormalities were most severe during the postnatal period, markedly improving by the time the pups were 2-4 weeks old. Despite the severe breathing dysfunction, many of these mice survived, but there was a high perinatal mortality, and those that survived had a decrease in growth rate until the age at which the respiratory defects resolved. Consistent with these in vivo observations, respiratory output was markedly reduced in isolated brainstem-spinal cord preparations from neonatal Lmx1b(f/f/p) mice and completely blocked in perfused brain preparations from neonatal rats treated with selective antagonists of 5-HT(2A) and neurokinin 1 (NK-1) receptors. The ventilatory deficits in neonatal Lmx1b(f/f/p) mice were reversed in vitro and in vivo with agonists of 5-HT(2A) and/or NK-1 receptors. These results demonstrate that ventilatory output in the neonatal period is critically dependent on serotonin neurons, which provide excitatory drive to the respiratory network via 5-HT(2A) and NK-1 receptor activation. These findings provide insight into the mechanisms of sudden infant death syndrome, which has been associated with abnormalities of 5-HT neurons and of cardiorespiratory control.
    Full-text · Article · Sep 2009 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Sudden infant death syndrome (SIDS) is postulated to result from abnormalities in brainstem control of autonomic function and breathing during a critical developmental period. Abnormalities of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS. To test the hypothesis that 5-HT receptor abnormalities in infants dying from SIDS are associated with decreased tissue levels of 5-HT, its key biosynthetic enzyme (tryptophan hydroxylase [TPH2]), or both. Autopsy study conducted to analyze levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); levels of TPH2; and 5-HT(1A) receptor binding. The data set was accrued between 2004 and 2008 and consisted of 41 infants dying from SIDS (cases), 7 infants with acute death from known causes (controls), and 5 hospitalized infants with chronic hypoxia-ischemia. Serotonin and metabolite tissue levels in the raphé obscurus and paragigantocellularis lateralis (PGCL); TPH2 levels in the raphé obscurus; and 5-HT(1A) binding density in 5 medullary nuclei that contain 5-HT neurons and 5 medullary nuclei that receive 5-HT projections. Serotonin levels were 26% lower in SIDS cases (n = 35) compared with age-adjusted controls (n = 5) in the raphé obscurus (55.4 [95% confidence interval {CI}, 47.2-63.6] vs 75.5 [95% CI, 54.2-96.8] pmol/mg protein, P = .05) and the PGCL (31.4 [95% CI, 23.7-39.0] vs 40.0 [95% CI, 20.1-60.0] pmol/mg protein, P = .04). There was no evidence of excessive 5-HT degradation assessed by 5-HIAA levels, 5-HIAA:5-HT ratio, or both. In the raphé obscurus, TPH2 levels were 22% lower in the SIDS cases (n = 34) compared with controls (n = 5) (151.2% of standard [95% CI, 137.5%-165.0%] vs 193.9% [95% CI, 158.6%-229.2%], P = .03). 5-HT(1A) receptor binding was 29% to 55% lower in 3 medullary nuclei that receive 5-HT projections. In 4 nuclei, 3 of which contain 5-HT neurons, there was a decrease with age in 5-HT(1A) receptor binding in the SIDS cases but no change in the controls (age x diagnosis interaction). The profile of 5-HT and TPH2 abnormalities differed significantly between the SIDS and hospitalized groups (5-HT in the raphé obscurus: 55.4 [95% CI, 47.2-63.6] vs 85.6 [95% CI, 61.8-109.4] pmol/mg protein, P = .02; 5-HT in the PGCL: 31.4 [95% CI, 23.7-39.0] vs 71.1 [95% CI, 49.0-93.2] pmol/mg protein, P = .002; TPH2 in the raphé obscurus: 151.2% [95% CI, 137.5%-165.0%] vs 102.6% [95% CI, 58.7%-146.4%], P = .04). Compared with controls, SIDS was associated with lower 5-HT and TPH2 levels, consistent with a disorder of medullary 5-HT deficiency.
    Full-text · Article · Feb 2010 · JAMA The Journal of the American Medical Association