Medizinische Universität Graz - Research portal
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SHR Neuro Cancer Cardio Lipid Metab Microb
Valko, PO; Gavrilov, YV; Yamamoto, M; Reddy, H; Haybaeck, J; Mignot, E; Baumann, CR; Scammell, TE.
Increase of histaminergic tuberomammillary neurons in narcolepsy.
Ann Neurol. 2013; 74(6):794-804
Doi: 10.1002/ana.24019
Web of Science
PubMed
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FullText_MUG
- Co-authors Med Uni Graz
- Haybäck Johannes
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- Abstract:
- ObjectiveNarcolepsy is caused by loss of the hypothalamic neurons producing the orexin/hypocretin neuropeptides. One key target of the orexin system is the histaminergic neurons of the tuberomammillary nucleus (TMN), an essential wake-promoting system. As cerebrospinal fluid histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in 2 mouse models of narcolepsy. MethodsWe counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone, and histamine in 7 narcolepsy patients and 12 control subjects using stereological techniques. We identified histaminergic neurons using immunostaining for histidine decarboxylase. We also examined these systems in 6 wild-type mice, 6 orexin/ataxin-3 transgenic mice, and 5 orexin ligand knockout mice. ResultsCompared to controls, narcolepsy patients had 94% more histaminergic TMN neurons (233,57249,476 vs 120,455 +/- 10,665, p<0.001). This increase was higher in 5 narcolepsy patients with >90% orexin neuron loss than in 2 patients with 75% orexin neuron loss (252,279 +/- 46,264 vs 186,804 +/- 1,256, p=0.03). Similarly, the number of histaminergic TMN neurons was increased 53% in orexin ligand knockout mice compared to wild-type mice, whereas orexin/ataxin-3 transgenic mice showed an intermediate 28% increase. InterpretationThis surprising increase in histaminergic neurons in narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons and may contribute to some of the symptoms of narcolepsy such as preserved consciousness during cataplexy and fragmented nighttime sleep. In addition, this finding may have therapeutic implications, as medications that enhance histamine signaling are now under development. Ann Neurol 2013;74:794-804
- Find related publications in this database (using NLM MeSH Indexing)
- Aged -
- Aged, 80 and over -
- Animals -
- Cell Count - methods
- Disease Models, Animal -
- Female -
- Histamine - physiology
- Humans -
- Hypothalamic Area, Lateral - cytology
- Hypothalamic Hormones - metabolism
- Intracellular Signaling Peptides and Proteins - genetics
- Male -
- Melanins - metabolism
- Mice -
- Mice, Inbred C57BL -
- Mice, Knockout -
- Mice, Transgenic -
- Middle Aged -
- Narcolepsy - metabolism
- Neurons - physiology
- Neuropeptides - genetics
- Nuclear Proteins - genetics
- Pituitary Hormones - metabolism
- Transcription Factors - genetics