Prenatal Hypoxia Induces Cl– Cotransporters KCC2 and NKCC1 Developmental Abnormality and Disturbs the Influence of GABAA and Glycine Receptors on Fictive Breathing in a Newborn Rat

Abstract

Prenatal hypoxia is a recognised risk factor for neurodevelopmental disorders associated with both membrane proteins involved in neuron homeostasis, e.g., chloride (Cl–) cotransporters, and alterations in brain neurotransmitter systems, e.g., catecholamines, dopamine, and GABA. Our study aimed to determine whether prenatal hypoxia alters central respiratory drive by disrupting the development of Cl– cotransporters KCC2 and NKCC1. Cl– homeostasis seems critical for the strength and efficiency of inhibition mediated by GABAA and glycine receptors within the respiratory network, and we searched for alterations of GABAergic and glycinergic respiratory influences after prenatal hypoxia. We measured fictive breathing from brainstem in ex vivo preparations during pharmacological blockade of KCC2 and NKCC1 Cl– cotransporters, GABAA, and glycine receptors. We also evaluated the membrane expression of Cl– cotransporters in the brainstem by Western blot and the expression of Cl– cotransporter regulators brain-derived neurotrophic factor (BDNF) and calpain. First, pharmacological experiments showed that prenatal hypoxia altered the regulation of fictive breathing by NKCC1 and KCC2 Cl– cotransporters, GABA/GABAA, and glycin. NKCC1 inhibition decreased fictive breathing at birth in control mice while it decreased at 4 days after birth in pups exposed to prenatal hypoxia. On the other hand, inhibition of KCC2 decreased fictive breathing 4 days after birth in control mice without any change in prenatal hypoxia pups. The GABAergic system appeared to be more effective in prenatal hypoxic pups whereas the glycinergic system increased its effectiveness later. Second, we observed a decrease in the expression of the Cl– cotransporter KCC2, and a decrease with age in NKCC1, as well as an increase in the expression of BDNF and calpain after prenatal hypoxia exposure. Altogether, our data support the idea that prenatal hypoxia alters the functioning of GABAA and glycinergic systems in the respiratory network by disrupting maturation of Cl– homeostasis, thereby contributing to long-term effects by disrupting ventilation.

The correlation between vitamin D3 and arginine metabolism levels in newborns with amino acid metabolism disorders

“…Andrea et al [12] explored the clinical value of Arg with pregnant women as the research object; The results showed that abnormal Arg could affect the maternal and fetal hemodynamic status and increase the risk of adverse maternal and fetal outcomes; As a double base amino acid, Arg is not a necessary amino acid for adults; However, in some cases, if the body is not yet mature and the body is under inflammatory stress, the abnormal expression of Arg is difficult to maintain the normal physiological function and positive nitrogen balance of the body; And for infants (especially premature infants), abnormal Arg expression can affect their growth and development. Olivier et al [13] confirmed in mouse experiments that for those with weakened hepatic enzyme metabolic activity, insufficient synthetase content, immature liver development, and low body mass, in vivo stress regulation can cause changes in Gly content. Mohammed et al [14] found that Gly levels in children with congenital metabolic defects decreased abnormally, which is consistent with the results of this study, confirming that Gly is an important precursor for the synthesis of glutathione, which can promote protein synthesis, reduce the degree of oxidative stress damage, and play an important role in the growth and proliferation of the intestinal epithelium.…”

<b><i>Slc6a13</i></b> Deficiency Attenuates <b><i>Pasteurella multocida</i></b> Infection-Induced Inflammation via Glycine-Inflammasome Signaling

“…In this study, the expression of GlyTs and GlyRs was also detected, and it was found that the expression of Slc6a9 and Glra4 in KO mice and macrophages is increased. GlyR activation is known to be as-sociated with Cl − flux [57], while GlyT is a Na + /Cl − -dependent membrane receptor [58]. Moreover, glycine acts as an co-agonist of N-methyl-D-aspartic acid receptor that can affect Na + and Ca2 + flux [59], thus glycine may change intracellular ion flux through its transporter and/ or receptor, thereby affecting inflammasome activation.…”