Web Box 6.1 Serotonin and Sudden Infant Death Syndrome: Is There a Link?

Sudden infant death syndrome (SIDS) is defined as “the sudden and unexpected death of an infant under 1 year of age, with the onset of the lethal episode apparently occurring during sleep, that remains unexplained after a thorough investigation including performance of a complete autopsy and review of the circumstances of death” (Horne, 2019). The prevalence of SIDS in the United States has steadily declined since 1990 due to multiple public efforts to educate parents on safe sleep practices for their babies. Nevertheless, this disorder remains the leading cause of death in infants between 1 month and 1 year of age, with about 1,400 deaths yearly (Centers for Disease Control and Prevention, 2020). As with many disorders, multiple factors are thought to contribute to the risk for SIDS. The most prominent theory describing these factors is the Triple Risk model of Filiano and Kinney (1994). This model proposes that the greatest risk for SIDS occurs when the following three conditions are met: (1) a critical period of development, namely the first year of life; (2) an underlying vulnerability of the infant, particularly a deficiency in cardiorespiratory functioning (integrated regulation of the cardiovascular and respiratory systems); and (3) an exogenous “stressor,” such as a prone sleeping position or covering the face of the infant.

Although the mechanisms of SIDS vulnerability are still being debated, one longstanding hypothesis is that infants dying from this condition suffer from deficient respiratory control leading to symptoms such as breath holding and lack of normal arousal in response to reduced blood oxygen (O2) levels (hypoxia) and elevated carbon dioxide (CO2) levels (hypercapnia). Hypoxia and/or hypercapnia can be caused by an extended period of apnea (cessation of breathing), prolonged rebreathing of exhaled air, or airway obstruction, all of which are most likely to occur during sleep. Whereas episodes of hypoxia and hypercapnia cause arousal and gasping for air (termed “autoresuscitation”) in healthy infants, these responses are thought to be inadequate or absent in cases of SIDS, thereby leading to death by asphyxia.

The strongest evidence for an involvement of 5-HT in SIDS comes from experimental studies of infant mice and rats. A substantial body of research has shown that during early infancy in these animals, brainstem serotonergic neurons are necessary both for normal breathing patterns and for the responses to elevated CO2 levels (Hodges et al., 2009; Hodges and Richerson, 2010; Cummings et al., 2011; Dosumu-Johnson et al., 2018). This is illustrated in Figure 1, which not only depicts a long apneic episode in a 4-day-old transgenic mouse lacking central serotonergic neurons but also shows a restoration of more normal breathing following administration of the 5-HT2A agonist DOI. These results implicate the lack of 5-HT2A receptor activation in the abnormal breathing patterns in animals deficient in serotonergic neurotransmission. It appears that the serotonergic neurons themselves detect the changes in CO2, probably because of the reduced blood pH caused by production of carbonic acid when CO2 is dissolved in an aqueous medium like blood. Additional evidence indicates that a caudal group of serotonergic neurons in the medulla mediate the respiratory response to hypercapnia, whereas the DRN neurons are responsible for the arousing effects of this condition (Corcoran et al., 2009; Smith et al., 2018). Yet another key observation from the rodent studies is that the dependence on 5-HT for adequate respiratory control is limited to infancy, because loss of serotonergic function does not impair breathing in older animals. This may help explain the critical developmental period for SIDS in human infants.

A figure with three graphs is shown. Graph A: The frequency variation for a normal wild-type mouse is depicted, with waves that are spiky and dense, with alternating patterns of constant amplitude and increasing amplitude, while the frequency range remains constant throughout. Graph B: The frequency variation for L m x 1 b superscript f slash f slash p mouse is depicted, where the wave is consecutive with increasing amplitude for a specific time frame, and then it remains constant with zero amplitude for the following 35 seconds, and then drops with consecutive waves of lower amplitude. Graph C: The frequency variation for L m x 1 b superscript f slash f slash p mouse after D O I administration is depicted, with the wave remaining with less amplitude for the maximum time period, then increasing and remaining moderate for the last 10 seconds.

Figure 1 Apnea in a neonatal mutant mouse lacking central serotonergic neurons Top trace illustrates the normal breathing pattern of a 4-day-old wild-type mouse. Each deflection from the horizontal line shows a breath except for clusters of higher-amplitude deflections, which represent vocalizations. The middle trace shows the breathing pattern of a transgenic mouse of the same age that lacks central serotonergic neurons (the mutant genetic construct is denoted as Lmx1bf/f/p). Note the 35-second period of apnea during which no breathing occurred. The bottom trace demonstrates that administration of the 5-HT2A agonist DOI to the mutant mice led to a more normal breathing pattern as shown by the absence of apneic episodes. (After Hodges and Richerson, 2010.)

While the experimental animal studies convincingly implicate the serotonergic system in respiratory control during infancy, there remains the key question of whether abnormalities in this system are present in babies who die from SIDS. Answering this question relies heavily on post-mortem studies of the brains of these babies, an effort that has been led for many years by Hannah Kinney and her coworkers at Boston Children’s Hospital. These studies found significant reductions in 5-HT and TPH2 levels and in 5-HT1A receptor binding in medullary raphe nuclei (reviewed in Kinney and Hayes, 2019). Because of the presence of serotonergic cell bodies in the areas examined, much of the decrease in 5-HT1A receptor binding could represent loss of somatodendritic serotonergic autoreceptors. Taken together, results from the animal and human studies have led to the hypothesis of a core serotonergic defect in a subset of SIDS babies (Cummings and Hodges, 2019; Kinney and Hayes, 2019). However, SIDS almost certainly has multiple causes. Clear serotonergic abnormalities are not present in all SIDS cases, in addition to which numerous findings of other (i.e., non-serotonergic) abnormalities in the brains of SIDS infants have been reported (Bright et al., 2018).

References

Bright, F.M., Vink, R., and Byard, R.W. (2018). Neuropathological developments in sudden infant death syndrome. Pediatr. Dev. Pathol., 21, 515–521.

Centers for Disease Control and Prevention (2020). Sudden Unexpected Infant Death and Sudden Infant Death Syndrome. Data and Statistics. https://www.cdc.gov/sids/data.htm, accessed July 9, 2020.

Corcoran, A.E., Hodges, M.R., Wu, Y., Wang, W., Wylie, C.J., Deneris, E.S., and Richerson, G.B. (2009). Medullary serotonin neurons and central CO2 chemoreception. Respir. Physiol. Neurobiol., 168, 49–58.

Cummings, K.J., Hewitt, J.C., Li, A., Daubenspeck, J.A., and Nattie, E.E. (2011). Postnatal loss of brain serotonin neurones compromises the ability of neonatal rats to survive episodic severe hypoxia. J. Physiol., 589, 5247–5256.

Cummings, K.J., and Hodges, M.R. (2019). The serotonergic system and the control of breathing during development. Respir. Physiol. Neurobiol., 270:103255. doi: 10.1016/j.resp.2019.103255.

Dosumu-Johnson, R.T., Corcoran, A.E., Chang, Y, Nattie, E., and Dymecki, S.M. (2018). Acute perturbation of Pet1-neuron activity in neonatal mice impairs cardiorespiratory homeostatic recovery. eLife, 7:e37857. doi: 10.7554/eLife.37857.

Filiano, J.J., and Kinney, H.C. (1994). A perspective on neuropathologic findings in victims of the sudden infant death syndrome: The triple-risk model. Biol. Neonate, 65, 194–197.

Hodges, M. R. and Richerson, G. B. (2010). The role of medullary serotonin (5-HT) neurons in respiratory control: Contributions to eupneic ventilation, CO2 chemoreception, and thermoregulation. J. Appl. Physiol., 108, 1425–1432.

Hodges, M.R., Wehner, M., Aungst, J., Smith, J.C., and Richerson, G.B. (2009). Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development. J. Neurosci., 29, 10341–10349.

Kinney, H.C., and Haynes, R.L. (2019). The serotonin brainstem hypothesis for the sudden infant death syndrome. J. Neuropathol. Exp. Neurol., 78, 765–779.

Horne, R.S.C. (2019). Sudden infant death syndrome: current perspectives. Int. Med. J., 49, 433–438.

Smith, H.R., Leibold, N.K., Rappoport, D.A., Ginapp, C.M., Purnell, B.S., Bode, N.M., Alberico, S.I., et al. (2018). Dorsal raphe serotonin neurons mediate CO2-induced arousal from sleep. J. Neurosci., 38, 1915–1925.

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