Loss of brainstem serotonergic neurons impairs autoresuscitation in neonate rats: is this relevant to the sudden infant death syndrome?

Sudden infant death syndrome, SIDS, remains the major cause of death among children less than a year old despite the identification of remediable environmental risk factors (air pollutants, nicotine, prone sleeping position, etc.). A plausible neurocentric hypothesis posits that these risk factors matter only in the context of some pre-existing brainstem neurological deficit (Becker, 1990). Specifically, cardiorespiratory collapse and death would result from defective brainstem mechanisms that have evolved to protect against stressors that occur while asleep during a critical period of development. The crux of the matter may be the phenomenon called autoresuscitation and the key to autoresuscitation is gasping, an intense but short-lived activation of breathing that restores blood gases in extremis. Gasping is presumably caused by the direct activation of the preBotzinger complex by hypoxia (Paton et al. 2006). The brainstem respiratory network is regulated by a multitude of extrinsic excitatory inputs (e.g. serotonin, catecholamines, substance P and orexin) besides the well-known chemoreceptor drive. Each of these substances can activate breathing and regularize the bursting frequency of the network especially under conditions when overall excitability is low (Doi & Ramirez, 2010). In mammals that are born at an early stage of brain development such as rodents and man, the brainstem respiratory network undergoes substantial postnatal maturation, breathing is more vulnerable and unstable during sleep and apnoeas are common. As a result of this instability, the tipping point between breathing resumption (and restoration of blood gases) and irreversible CNS hypoxic depression may be reached more easily in early infancy than later in life. In a recent issue of The Journal of Physiology, Cummings and colleagues (2011) show that autoresuscitation during exposure to repeated hypoxia episodes in neonate rats is compromised when the lower brainstem serotonergic neurons are lesioned a couple of days after birth. This experiment demonstrates that a deficit in the level of just one of the many neuromodulators that sustain breathing makes a critical difference in the newborn animal's ability to survive repeated hypoxic stresses. The observation is congruent with the fact that mice in which most serotonergic neurons fail to develop also have an increased vulnerability to hypoxic stress (Erickson & Sposato, 2009). Cummings et al. (2011) destroyed the serotonergic neurons after birth, they limited the destruction to the lower brainstem and they kept the rats under thermoneutral conditions, demonstrating that the respiratory deficit was not caused by a prenatal change in brain development or by a deficit in thermoregulation which could also be expected from a lesion of these serotonergic neurons (Morrison et al. 2008). Is this observation relevant to SIDS? In a general sense, yes, because it illustrates how a relatively small deficit in lower brainstem circuitry that is inconsequential under ordinary circumstances, compromises an animal's ability to survive repeated hypoxic episodes during the neonatal period. Does this observation imply that a serotonergic deficiency is a likely explanation for SIDS? The answer to this question has to be much more nuanced because, at least in the personal opinion of the author of this editorial, the supportive human evidence, of a neuropathological nature, conveys mixed signals. Postmortem analysis of the brainstem of SIDS victims has uncovered a host of hard to interpret brainstem anomalies including gliosis, the persistence of an immature neuronal dendritic branching pattern, abnormal levels of receptors to various transmitters, possible defects in catecholaminergic neurons and hypoplasia of the ventral medullary arcuate nucleus (not to be confused with the hypothalamic homonym), a nucleus whose function is unknown and purported homology with the respiratory chemosensory region at the ventral medullary surface of lower mammals is pure speculation. Many anomalies of the serotonergic system have also been reported. A large increase in a subset of serotonergic cell bodies with simple (‘granular’) morphology was interpreted as evidence of an underlying developmental disorder involving excessive numbers and delayed maturation of serotonergic neurones (Paterson et al. 2006). This tantalizing result needs to be confirmed with contemporary stereological methods. Reduced levels of serotonin and tryptophan hydroxylase were also found (Duncan et al. 2010) which could suggest serotonergic neuron hypoactivity although a reduction in steady-state transmitter content can also be a sign of increased release. The now-confirmed reduction in presumed 5-HT1A heteroreceptors (receptors located outside the raphe) could conceivably render the respiratory network more vulnerable to hypoxic depression since the activation of these receptors stimulates breathing under specific circumstances (opiate administration) (Manzke et al. 2010). On the other hand, the deficit in 5-HT1A autoreceptors (Paterson et al. 2006; Duncan et al. 2010) could be viewed as evidence that serotonin release is excessive rather than depressed given the restraining influence of these receptors on the activity of the serotonergic neurons (Innis & Aghajanian, 1987). In sum, the present study (Cummings et al. 2011) demonstrates that a lesion of lower brainstem serotonergic neurons interferes with autoresuscitation in neonate rats. By extension, this evidence suggests that some brainstem defect might also contribute to SIDS. Although the neuropathology literature clearly shows that SIDS is not caused by a massive loss of lower brainstem serotonergic neurons, this body of work suggests that a more subtle defect in serotonergic transmission could be a predisposing factor.