title: Increase of histaminergic tuberomammillary neurons in narcolepsy.
abstract: OBJECTIVE
  Narcolepsy 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Compared to controls, narcolepsy patients had 94% more histaminergic TMN neurons (233,572 ± 49,476 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA; Department of Neurology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Philipp O
authors.initials: PO
authors.lastname: Valko
authors.forename: Yury V
authors.initials: YV
authors.lastname: Gavrilov
authors.forename: Mihoko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hasini
authors.initials: H
authors.lastname: Reddy
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
authors.forename: Christian R
authors.initials: CR
authors.lastname: Baumann
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Scammell
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000067699:Ataxin-3; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D006632:Histamine / Q000502:physiology*; D006801:Humans; D007026:Hypothalamic Area, Lateral / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D007028:Hypothalamic Hormones / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008543:Melanins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009290:Narcolepsy / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D000068797:Orexins; D010907:Pituitary Hormones / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D007028:Hypothalamic Hormones; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins; D010907:Pituitary Hormones; D014157:Transcription Factors; C019463:melanin-concentrating hormone; D006632:Histamine; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse