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Increase of histaminergic tuberomammillary neurons in narcolepsy
Author(s) -
Valko Philipp O.,
Gavrilov Yury V.,
Yamamoto Mihoko,
Reddy Hasini,
Haybaeck Johannes,
Mignot Emmanuel,
Baumann Christian R.,
Scammell Thomas E.
Publication year - 2013
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24019
Subject(s) - histaminergic , narcolepsy , orexin , endocrinology , cataplexy , medicine , histidine decarboxylase , neuropeptide , histamine , biology , neuroscience , receptor , neurology , biochemistry , amino acid , histidine
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. Interpretation 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. Ann Neurol 2013;74:794–804