Proton- and ammonium-sensing by histaminergic neurons controlling wakefulness

The histaminergic neurons in the tuberomamillary nucleus (TMN) of the posterior hypothalamus are involved in the control of arousal. These neurons are sensitive to hypercapnia as has been shown in experiments examining c-Fos expression, a marker for increased neuronal activity. We investigated the mechanisms through which TMN neurons respond to changes in extracellular levels of acid/CO2. Recordings in rat brain slices revealed that acidification within the physiological range (pH from 7.4 to 7.0), as well as ammonium chloride (5 mM), excite histaminergic neurons. This excitation is significantly reduced by antagonists of type I metabotropic glutamate receptors and abolished by benzamil, an antagonist of acid-sensing ion channels (ASICs) and Na+/Ca2+ exchanger, or by ouabain which blocks Na+/K+ ATPase. We detected variable combinations of 4 known types of ASICs in single TMN neurons, and observed activation of ASICs in single dissociated TMN neurons only at pH lower than 7.0. Thus, glutamate, which is known to be released by glial cells and orexinergic neurons, amplifies the acid/CO2-induced activation of TMN neurons. This amplification demands the coordinated function of metabotropic glutamate receptors, Na+/Ca2+ exchanger and Na+/K+ ATPase. We also developed a novel HDC-Cre transgenic reporter mouse line in which histaminergic TMN neurons can be visualized. In contrast to the rat, the mouse histaminergic neurons lacked the pH 7.0-induced excitation and displayed only a minimal response to the mGluR I agonist DHPG (0.5 μM). On the other hand, ammonium-induced excitation was similar in mouse and rat. These results are relevant for the understanding of the neuronal mechanisms controlling acid/CO2-induced arousal in hepatic encephalopathy and obstructive sleep apnoea. Moreover, the new HDC-Cre mouse model will be a useful tool for studying the physiological and pathophysiological roles of the histaminergic system

New perspectives in eosinophilic granulomatosis with polyangiitis (EGPA): report of the first meeting of the European EGPA Study Group

The European Eosinophilic Granulomatosis with Polyangiitis (EGPA) study group first gathered in Firenze in December 2018. The discussion was centred around the clinical and therapeutic needs in EGPA which still remain unmet. Indeed, EGPA is a puzzling and rare disease which shares clinical features with other anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs) and hypereosinophilic syndromes (HESs). Some of the recommendations published in 2015 are based on data derived from EGPA-related diseases, rather than from EGPA itself, and therefore need to be updated. Thus, the aim of the meeting was to stimulate ongoing research, to promote collaborative European studies and to define the main issues on which future studies should be focused. Current fields of research on EGPA include potential serological biomarkers of disease activity and of specific organ involvement, possible links between different genetic variants and clinical phenotypes, and new therapeutic perspectives. Herein, we give an overview of the meeting with the goal to stimulate an international collaboration and new points of discussion