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Hyperbilirubinemia is associated with multiple morbidities including apnea of prematurity in preterm infants. Bilirubin, a byproduct of hemoglobin breakdown, is not excreted normally and results in high circulating levels giving rise to a state of hyperbilirubinemia. Free bilirubin (not bound to albumin) can cross the blood-brain barrier and be neurotoxic. Prior studies have shown that a systemic injection of bilirubin accumulates in the brainstem and is associated with an impaired ventilatory response to hypercapnia and an augmented hypoxic ventilatory depression. Here, using the Gunn rat model of endogenous hyperbilirubinemia, we investigated its effects on the excitability of neurons of the nucleus tractus solitarius (NTS). The homozygous Gunn rat (jj) model of hyperbilirubinemia 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 received either a 200mg/kg intraperitoneal injection of sulfadimethoxine (SDMX), which dissociates bilirubin from albumin resulting in increased levels of circulating free bilirubin, or an equivalent amount of saline as a vehicle control. Whole cell patch clamp was performed on NTS neurons two days later (P7) to assess characteristics of evoked excitatory postsynaptic currents (eEPSC).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 (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, p<0.05). Comparison of failure rate of jj+saline to Nj+saline (6.63%±3.12, p<0.05) was also statistically significant. The hyper-responsive NTS neurons of jj+saline rats may be an adaptive response to the deleterious effects of circulating (bound and unbound) bilirubin. However, the impaired response of neurons in jj+SDMX rats may reflect neurotoxic effects of increased free bilirubin 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. William and Lois Briggs Endowment. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Mayer et al. (Wed,) studied this question.