Brainstem Serotonergic Deficiency in Sudden Infant Death Syndrome

Department of Pathology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 02/2010; 303(5):430-7. DOI: 10.1001/jama.2010.45
Source: PubMed


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.

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    • "The failure to arouse may also prevent a life-saving shift in body position that would otherwise free obstructed airways (Garcia et al., 2013). The brainstem cholinergic system, the RTN, peripheral chemoreceptors , and brainstem serotonergic neurons have been judged abnormal in some cases of SIDS (Duncan et al., 2010; Lavezzi et al., 2012; Peñ a et al., 2004; Porzionato et al., 2013); however, defects of the serotonergic system may be most critical. Transgenic mice lacking serotonin neurons have high mortality during development, severe neonatal apneas (Hodges et al., 2009), and fail to arouse when exposed to CO 2 (Buchanan and Richerson, 2010). "
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    ABSTRACT: Recent advances have clarified how the brain detects CO2 to regulate breathing (central respiratory chemoreception). These mechanisms are reviewed and their significance is presented in the general context of CO2/pH homeostasis through breathing. At rest, respiratory chemoreflexes initiated at peripheral and central sites mediate rapid stabilization of arterial PCO2 and pH. Specific brainstem neurons (e.g., retrotrapezoid nucleus, RTN; serotonergic) are activated by PCO2 and stimulate breathing. RTN neurons detect CO2 via intrinsic proton receptors (TASK-2, GPR4), synaptic input from peripheral chemoreceptors and signals from astrocytes. Respiratory chemoreflexes are arousal state dependent whereas chemoreceptor stimulation produces arousal. When abnormal, these interactions lead to sleep-disordered breathing. During exercise, central command and reflexes from exercising muscles produce the breathing stimulation required to maintain arterial PCO2 and pH despite elevated metabolic activity. The neural circuits underlying central command and muscle afferent control of breathing remain elusive and represent a fertile area for future investigation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 09/2015; 87(5):946-61. DOI:10.1016/j.neuron.2015.08.001 · 15.05 Impact Factor
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    • "We chose an intermittent hypercapnic stimulus, as chronic hypercapnia is shown to attenuate subsequent hypercapnic sensitivity (Bavis et al., 2006; Dempsey and Forster, 1982; Kondo et al., 2000; Lai et al., 1981; Rezzonico et al., 1990; Rezzonico and Mortola, 1989; Schaefer et al., 1963). Abnormal serotonergic brainstem mechanisms may contribute to infant vulnerability to Sudden Infant Death Syndrome (SIDS), and that vulnerability may result in part from chemosensory dysfunction (Cummings et al., 2009; Duncan et al., 2010; Hodges and Richerson, 2010; Kinney et al., 2009; Paterson et al., 2006; Richerson, 2004). If induced reflex plasticity is sufficient to overcome or reverse ventilatory chemosensitivity dysfunctions similar to those thought to contribute to SIDS, then interventions that induce plasticity could be therapeutic in augmenting chemoresponsiveness and decreasing infant vulnerability to SIDS. "
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    ABSTRACT: Serotonergic dysfunction compromises ventilatory chemosensitivity and may enhance vulnerability to pathologies such as the Sudden Infant Death Syndrome (SIDS). We have shown raphé contributions to central chemosensitivity involving serotonin (5-HT)-and γ-aminobutyric acid (GABA)-mediated mechanisms. We tested the hypothesis that mild intermittent hypercapnia (IHc) induces respiratory plasticity, due in part to strengthening of GABA mechanisms. Rat pups were IHc-pretreated (8 consecutive cycles; 5min 5% CO2 - air, 10min air) or constant normocapnia-pretreated as a control, each day for 5 consecutive days beginning at P12. We subsequently assessed CO2 responsiveness using the in situ perfused brainstem preparation. Hypercapnic responses were determined with and without pharmacological manipulation. Results show IHc-pretreatment induces plasticity sufficient for responsiveness despite removal of otherwise critical ketanserin-sensitive mechanisms. Responsiveness following IHc-pretreatment was absent if ketanserin was combined with GABAergic antagonism, indicating that plasticity depends on GABAergic mechanisms. We propose that IHc-induced plasticity could reduce the severity of reflex dysfunctions underlying pathologies such as SIDS.
    Respiratory Physiology & Neurobiology 05/2014; 200. DOI:10.1016/j.resp.2014.05.005 · 1.97 Impact Factor
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    • "nature of diseases believed to result from failures in chemosensitivity, such as sleep apnea, congenital central hypoventilation syndrome (CCHS), sudden unexplained death in epilepsy (SUDEP), and sudden infant death syndrome (SIDS). In particular, vulnerability to SIDS is proposed to occur as a result of brainstem serotonergic dysfunction (Paterson et al. 2006; Kinney et al. 2009; Kinney and Thach 2009; Duncan et al. 2010). However, it is not known how this dysfunction contributes to these pathologies. "
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    Journal of Neurophysiology 09/2013; 110(11). DOI:10.1152/jn.00288.2013 · 2.89 Impact Factor
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