Abnormalities in substance P neurokinin-1 receptor binding in key brainstem nuclei in sudden infant death syndrome related to prematurity and sex

Abstract

Sudden infant death syndrome (SIDS) involves failure of arousal to potentially life threatening events, including hypoxia, during sleep. While neuronal dysfunction and abnormalities in neurotransmitter systems within the medulla oblongata have been implicated, the specific pathways associated with autonomic and cardiorespiratory failure are unknown. The neuropeptide substance P (SP) and its tachykinin neurokinin-1 receptor (NK1R) have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation, integration of cardiovascular control, and modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may therefore result in autonomic dysfunction during sleep and contribute to SIDS deaths. [125I] Bolton Hunter SP autoradiography was used to map the distribution and density of the SP, NK1R to 13 specific nuclei intimately related to cardiorespiratory function and autonomic control in the human infant medulla of 55 SIDS and 21 control (non-SIDS) infants. Compared to controls, SIDS cases exhibited a differential, abnormal developmental profile of the SP/NK1R system in the medulla. Furthermore the study revealed significantly decreased NK1R binding within key medullary nuclei in SIDS cases, principally in the nucleus tractus solitarii (NTS) and all three subdivisions of the inferior portion of the olivo-cerebellar complex; the principal inferior olivary complex (PIO), medial accessory olive (MAO) and dorsal accessory olive (DAO). Altered NK1R binding was significantly influenced by prematurity and male sex, which may explain the increased risk of SIDS in premature and male infants. Abnormal NK1R binding in these medullary nuclei may contribute to the defective interaction of critical medullary mechanisms with cerebellar sites, resulting in an inability of a SIDS infant to illicit appropriate respiratory and motor responses to life threatening challenges during sleep. These observations support the concept that abnormalities in a multi-neurotransmitter network within key nuclei of the medullary homeostatic system may underlie the pathogenesis of a subset of SIDS cases.

Fig 1. Autoradiographic grey scale images of ¹²⁵I Bolton Hunter SP binding to NK1R receptors in transverse sections of the caudal and rostral human infant medulla.

Red boundary contour delineates the 13 target nuclei.

Fig 2. Normative distribution and density of mean total NK1R binding (fmol/mg) in the human infant medulla of non-SIDS controls.

Fig 3. Consistent significant absolute reductions in NK1R binding (fmol/mg) in SIDS cases compared to non-SIDS controls.

a. NK1R binding SIDS vs. acute controls. Compared to acute controls, NK1R binding was significantly reduced in SIDS cases in the NTS (p = 0.04), DAO (p = 0.01) and MAO (p = 0.03), b. NK1R binding in SIDS vs. combined controls. NK1R binding was significantly reduced in SIDS cases in the DAO (p = 0.01) and MAO (p = 0.03) with borderline significance in the PIO (p = 0.09) when compared to all controls combined (acute, chronic and hypoxic).c. Autoradiograms displaying NK1R binding (fmol/mg) in the NTS nuclei. Absolute reductions in NK1R binding were consistently observed in SIDS cases. d. Autoradiograms displaying NK1R binding (fmol/mg) in component nuclei of the IO. NK1R binding was consistently reduced in SIDS cases. *p = <0.05, **p = <0.01.

Fig 4. NK1R binding by PCA across diagnoses in multiple medullary nuclei.

Fig 5

a. Significant effect of prematurity on NK1R binding in key medullary nuclei in term and premature non-SIDS controls vs. no effect in term compared to premature SIDS cases. b. Signficaint differences in NK1R binding in premature SIDS cases compared to premature controls in key medullary nuclei. *p = <0.05, **p = <0.01.

Fig 6. Marked sex effect on NK1R binding observed in the IO nuclei in male SIDS cases.

*p = <0.05, ***p<0.001.