Thyroid hormone deficiency potentiates GABAergic inhibition of the brainstem respiratory network in newborn rat

Abstract

Because thyroid hormones (THs) are present in the brainstem and are essential for both the differentiation of the presynaptic GABAergic neurons and the maturation of the postsynaptic components of the GABAergic system, we proposed that TH deficiency during gestation is sufficient to disrupt GABAergic modulation of the brainstem's respiratory network in newborn rats. Thyroid hormone deficiency in the foetus was recreated by administrating an antithyroid susbstance (Methimazole;MMI) in drinking water of the pregnant dam at concentration of 0,02% (weight per volume; w/v) from the first day of pregnancy (gestational day 1; GD1) to the day of experiment with the newborn. In‐vitro measurements were performed on Sprague Dawley rats aged of 4 days. Fictive breathing (in‐vitro) was measured by extracting the brainstem with a part of the spinal cord and placing it in a chamber where it was superfused with an artificial cerebrospinal fluid (aCSF). The output signal from the respiratory network was recorded by a suction electrode placed on the fourth ventral root representing the inspiratory signal sent to the diaphragm via the phrenic nerve. Compared to controls, pups from MMI treated dams showed 69% decreased phrenic burst frequency under baseline conditions (5.5 ± 0.4 vs 8.0 ± 0.4 bursts/min; treatment effect: P=0.0003). Moreover, they presented an increased dose‐dependent depression of fictive breathing following Muscimol application (GABAA receptor agonist) (dose 0.1μM: −27 ± 7.9 vs −7.8 ± 3.4 % change from baseline; treatment effect: P=0.0233) and increased elevation of phrenic burst frequency following Bicuculline exposure (GABAA receptor antagonist) (dose 8μM: 25.4 ± 5.3 vs 5.3 ± 3.9 % change from baseline; treatment effect P=0.0085). This treatment‐dependent augmentation of GABAergic tone did not affect burst amplitude, thus indicating that the role of TH on GABAergic modulation is selective. We conclude that TH deficiency results in an increased GABAergic inhibition in the core elements of the respiratory control circuit which could explain the reduced phrenic bursts frequency observed in the treated pups. These results provide new hypotheses regarding the origins of respiratory disorders of the newborn involving reduced respiratory drive such as apnea of prematurity.Support or Funding InformationSupported by NSERC.