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.