Inflammation-induced release of prostaglandin E2 (PGE2) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE2. This alters neural network activity in the preBötzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R+/+ cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspiration and sighs throughout life, and the ability to autoresuscitate when breathing fails.DOI: http://dx.doi.org/10.7554/eLife.14170.001

Nurr1, a transcription factor belonging to the family of nuclear receptors, is expressed at high levels immediately after birth. Gene-targeted mice lacking Nurr1 fail to develop midbrain dopaminergic neurones and do not survive beyond 24 h after birth. Dopamine (DA) levels may be regulated by Nurr1, and as DA is involved in both central and peripheral respiratory control, we hypothesized that lack of Nurr1 may impair breathing and cause death by respiratory failure. We demonstrate herein that Nurr1 newborn knockout mice have a severely disturbed breathing pattern characterized by hypoventilation, numerous apnoeas and failure to increase breathing when challenged with hypoxia. In heterozygote Nurr1 mice the response to hypoxia is also altered. Furthermore, the central respiratory rhythm, generated from isolated brainstem-spinal cord preparations, exhibits impaired response to hypoxia in mice lacking Nurr1. Moreover, Nurr1 is expressed in several respiratory-related regions of the nervous system, including the nucleus of the solitary tract, the nucleus ambiguus and the dorsal motor nucleus of the vagus nerve, and in the carotid bodies. The prominent Nurr1 expression in these areas, involved in respiratory control, along with the severe respiratory phenotype, indicates that Nurr1 plays a major role in the extrauterine adaption of respiratory control and the response to hypoxia.

The effects of substance P (SP) on respiratory activity in the brainstem-spinal cord preparation from neonatal rats (0-4 days old) were investigated. The respiratory activity was recorded from C4 ventral roots and intracellularly from three types of respiration-related neurones, i.e. pre-inspiratory (or biphasic E), three subtypes of inspiratory; expiratory and tonic neurones in the ventrolateral medulla (VLM). After the onset of SP bath application (10 nM-1 microM) a dose-dependent decline of burst rate (by 48%) occurred, followed by a weaker dose-dependent increase (by 17.5%) in burst rate. The biphasic effect of SP on inspiratory burst rate was associated with sustained membrane depolarization (in a range of 0.5-13 mV) of respiration-related and tonic neurones. There were no significant changes in membrane resistance in any type of neurones when SP was applied alone or when synaptic transmission was blocked with tetrodotoxin (TTX). The initial depolarization was associated with an increase in inspiratory drive potential (by 25%) as well as in bursting time (by 65%) and membrane excitability in inspiratory and pre-inspiratory neurones, which corresponded to the decrease in burst rate (C4 activity). The spiking frequency of expiratory and tonic neurones was also increased (by 36 and 48%). This activation was followed by restoration of the synaptic drive potential and bursting time in inspiratory and to a less extent in pre-inspiratory neurones, which corresponded to the increase in burst rate. The discharge frequency of expiratory and tonic neurones also decreased to control values. This phase followed the peak membrane depolarization. At the peak depolarization, SP reduced the amplitude of the action potential by 4-8% in all types of neurones. Our results suggest that SP exerts a general excitatory effect on respiration-related neurones and synaptic coupling within the respiratory network in the VLM. The transient changes in neuronal activity in the VLM may underlie the biphasic effect of SP in the brainstem respiration activity recorded in C4 roots. However, the biphasic effect of SP on inspiratory burst rate seems to be also defined by the balance in activity of other SP-sensitive systems and neurones in the respiratory network in the brainstem and spinal cord, which can modify the activity of medullary respiratory rhythm generator.