586 - Impaired Neurotransmission in Brainstem Respiratory Control Regions in a Rat Model of Neonatal Hyperbilirubinemia

Poster Number: 586
Publication Number: 586.1420

Background: Hyperbilirubinemia is associated with apnea of prematurity and is linked to multiple morbidities in preterm infants. In these infants, bilirubin, a byproduct of hemoglobin breakdown, is not excreted normally and results in high circulating levels. Free bilirubin (not bound to albumin) can cross the blood-brain barrier and be neurotoxic. However, the effects of hyperbilirubinemia on the neural pathways involved in respiratory control are not known.

Objective: We used the Gunn rat model to investigate the impact of hyperbilirubinemia on neuronal function in the nucleus tractus solitarius (nTS), a center of respiratory neural processing.

Design/Methods: We used the homozygous Gunn rat (jj) model of hyperbilirubinemia because it lacks uridine diphosphate-glucuronosyltransferase-1A1, an enzyme which is needed to catabolize bilirubin. Heterozygous Nj Gunn rat pups were used for control. On postnatal (P) day 5, Nj and jj rat pups were treated intraperitoneally with 200mg/kg sulfadimethoxine (SDMX), which results in increased levels of circulating free bilirubin, or an equivalent volume of saline. Whole cell patch clamp was performed on nTS neurons two days later (P7) to assess the neuronal responses to stimulation.

Results: The amplitude of the evoked stimulus response to a 20Hz stimulus train was significantly increased in nTS neurons from jj+saline pups when compared to cells from Nj+saline and Nj+SDMX animals (Fig1A, p< 0.05). This increased amplitude was no longer present after SDMX treatment of jj pups. Additionally, jj+saline nTS neurons did not exhibit any failure to solitary tract stimulation, whereas SDMX treatment significantly increased the failure rate during a 20Hz stimulus train (jj+saline =0.0%±0.0, jj+SDMX= 18.63%±8.82) and when compared Nj+saline (6.63%±3.12) (Fig1B p< 0.05 for jj+saline vs Nj+saline and jj+SDMX).

Conclusion(s): The nTS neurons of jj+saline rats were hyper-responsive to stimulation which may be an adaptive response to deleterious effects of circulating (bound and unbound) bilirubin. However, the impaired response of neurons in jj+SDMX rats may reflect neurotoxicity from the increased free bilirubin (i.e. hyperbilirubinemia), leading to impaired neurotransmission. The latter is consistent with the high failure rate of nTS neurons in jj+SDMX rats. These data may have implications for impaired respiratory control mechanisms involved in mediating essential vagally mediated ventilatory defense responses to hypoxemia and may contribute to the apnea of prematurity associated with hyperbilirubinemia in preterm infants.