AMPK facilitates the hypoxic ventilatory response through non‑adrenergic mechanisms at the brainstem

We recently demonstrated that the hypoxic ventilatory response (HVR) is facilitated by the AMP-activated protein kinase (AMPK) in catecholaminergic neural networks that likely lie downstream of the carotid bodies within the caudal brainstem. Here we further subcategorise the neurons involved, by cross-comparison of mice in which the genes encoding the AMPK‑α1 ( Prkaa1 ) and AMPK‑α2 ( Prkaa2 ) catalytic subunits were deleted in catecholaminergic (TH-Cre) or adrenergic (PNMT-Cre) neurons. The HVR was markedly attenuated in mice with AMPK‑α1/α2 deletion in catecholaminergic neurons and modestly augmented in mice with AMPK‑α1/α2 deletion in adrenergic neurons when compared against a variety of controls (TH-Cre, PNMT‑Cre, AMPK‑α1/α2 floxed). Moreover, AMPK‑α1/α2 deletion in catecholaminergic neurons precipitated marked hypoventialtion and apnoea during poikilocapnic hypoxia, relative to controls, while mice with AMPK‑α1/α2 deletion in adrenergic neurons entered relative hyperventilation with reduced apnoea frequency and duration when compared to controls. We conclude, therefore, that AMPK facilitates the HVR through non‑adrenergic mechanisms, where adrenergic pathways may deliver weaker negative inputs.