Failed heart rate recovery at a critical age in 5-HT-deficient mice exposed to episodic anoxia: implications for SIDS

Abstract

Mice deficient in the transcription factor Pet-1⁻/⁻ have a ∼70% deficiency of brainstem serotonin [5-hydroxytryptamine (5-HT)] neurons and exhibit spontaneous bradycardias in room air at postnatal day (P)5 and P12 and delayed gasping in response to a single episode of anoxia at P4.5 and P9.5 (Cummings KJ, Li A, Deneris ES, Nattie EE. Am J Physiol Regul Integr Comp Physiol 298: R1333-R1342, 2010; and Erickson JT, Sposato BC. J Appl Physiol 106: 1785-1792, 2009). We hypothesized that at a critical age Pet-1⁻/⁻ mice will fail to autoresuscitate during episodic anoxia, ultimately dying from a failure of gasping to restore heart rate (HR). We exposed P5, P8, and P12 Pet-1⁻/⁻ mice and wild-type littermates (WT) to four 30-s episodes of anoxia (97% N₂-3% CO₂), separated by 5 min of room air. We observed excess mortality in Pet-1⁻/⁻ only at P8: 43% of Pet-1⁻/⁻ animals survived past the third episode of anoxia while ∼95% of WT survived all four episodes (P = 0.004). No deaths occurred at P5 and at P12, and one of six Pet-1⁻/⁻ mice died after the fourth episode, while all WT animals survived. At P8, dying Pet-1⁻/⁻ animals had delayed gasping, recovery of HR, and eupnea after the first two episodes of anoxia (P < 0.001 for each); death ultimately occurred when gasping failed to restore HR. Both high- and low-frequency components of HR variability were abnormally elevated in dying Pet-1⁻/⁻ animals following the first episode of anoxia. Dying P8 Pet-1⁻/⁻ animals had significantly fewer 5-HT neurons in the raphe magnus than surviving animals (P < 0.001). Our data indicate a critical developmental window at which a brainstem 5-HT deficiency increases the risk of death during episodes of anoxia. They may apply to the sudden infant death syndrome, which occurs at a critical age and is associated with 5-HT deficiency.

Developmental changes in GABAergic neurotransmission to presympathetic and cardiac parasympathetic neurons in the brainstem

“…Interestingly, 90% of the sudden infant deaths occur before 6 mo of age, with 75% of these deaths between 2 and 4 mo of age (Cummings et al 2011;Mathews and MacDorman 2008). Although human developmental age between 2 and 6 mo has been characterized as an unstable time for many physiological systems (Filiano and Kinney 1994;Willinger et al 1991), the developmental neurophysiological mechanisms underlying this unique period of vulnerability remains unknown (Hunt and Brouillette 1987).…”

“…Infants that succumb to SIDS typically experience a progressive bradycardia and hypotension during the lethal event (Fewell and Smith 1998;Harper 2000;Hunt and Brouillette 1987;Ledwidge et al 1998;Meny et al 1994), suggesting that sympathoinhibition and/or exaggerated parasympathetic activity to the heart could be likely mechanisms of SIDS (Harper 2000). In addition, hypoxia has been suggested to play an important role in SIDS (Cummings et al 2011). Indeed, postnatal risk factors for SIDS include exposure to noxious stimuli such as rebreathing of air which may result in H/H (Farrell et al 2002).…”

“…SIDS and other cardiorespiratory developmental disorders are often accompanied by apneas and episodes of hypoxia and hypercapnia (H/H) (Cummings et al 2011;Meny et al 1994;Poets et al 1999). In addition to their activity under control conditions, the activity of both PSNs and CVNs is strongly modulated by challenges such as H/H or hypoxia alone Kamendi et al 2009;Sun and Reis 1994a, b).…”

Proposal for mechanisms of protection of supine sleep against sudden infant death syndrome: an integrated mechanism review

“…Genetic factors and defects that contribute to the "underlying abnormality" are included as intrinsic factors. A common feature seen in rare instances where recordings are available during the death, is profound bradycardia with inadequate gasps (8,9), an adverse autonomic event from which there is a failure to autoresuscitate (10,11). The deficiency in serotonin and other related neurotransmitters and pathways are implicated in this failure (5), with effective gasping being "vulnerable to disruption by much smaller defects in multiple neurotransmitter systems" (page 533) (4).…”

Sudden Unexpected Death in Fetal Life Through Early Childhood

“…For example, the hypothesis that the underlying vulnerability is a failure in protective responses to hypoxia, hypercarbia, or hyperthermia in brainstem 5-HT pathways has been investigated by using several models of 5-HT brainstem deficiency. [88][89][90][91][92][93] These models include genetically engineered mice with reversibly "silenced" 5-HT neurons using the Designer Receptors Exclusively Activated by Designer Drugs technology. 93,94 In all of these 5-HT-deficient models, physiologic aberrations in responses to hypoxia, including in arousal and autoresuscitation, have been demonstrated, as have effects during sleep.…”