Histamine in murine narcolepsy: What do genetic and immune models tell us?

Abstract

An increased number of histaminergic neurons, identified by labeling histidine-decarboxylase (HDC) its synthesis enzyme, was unexpectedly found in patients with narcolepsy type 1 (NT1). In quest for enlightenment, we evaluate whether an increase in HDC cell number and expression level would be detected in mouse models of the disease, in order to provide proof of concepts reveling possible mechanisms of compensation for the loss of orexin neurons, and/or of induced expression as a consequence of local neuroinflammation, a state that likely accompanies NT1. To further explore the compensatory hypothesis, we also study the noradrenergic wake-promoting system. Immunohistochemistry for HDC, orexin, and melanin-concentrating hormone (MCH) was used to count neurons. Quantitative-PCR of HDC, orexin, MCH, and tyrosine-hydroxylase was performed to evaluate levels of mRNA expression in the hypothalamus or the dorsal pons. Both quantifications were achieved in genetic and neuroinflammatory models of narcolepsy with major orexin impairment, namely the orexin-deficient (Orex-KO) and orexin-hemagglutinin (Orex-HA) mice respectively. The number of HDC neurons and mRNA expression level were unchanged in Orex-KO mice compared to controls. Similarly, we found no change in tyrosine-hydroxylase mRNA expression in the dorsal pons between groups. Further, despite the presence of protracted local neuroinflammation as witnessed by the presence of reactive microglia, we found no change in the number of neurons nor the expression of HDC in Orex-HA mice compared to controls. Importantly, no correlation was found in all conditions between HDC and orexin. Our findings indicate that, in mice, the expression of histamine and noradrenalin, two wake-promoting systems, are not modulated by orexin level whether the lack of orexin is constitutive or induced at adult age, showing thus no compensation. They also show no recruitment of histamine by local neuroinflammation. Further studies will be needed to further define the role of histamine in the pathophysiology of NT1.

Keywords: hypocretin; hypothalamus; orexin; sleep.