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Increase of histaminergic tuberomammillary neurons in narcolepsy


Valko, P O; Gavrilov, Y V; Yamamoto, M; Reddy, H; Haybaeck, J; Mignot, E; Baumann, C R; Scammell, T E (2013). Increase of histaminergic tuberomammillary neurons in narcolepsy. Annals of Neurology, 74(6):794-804.

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 CSF histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in two mouse models of narcolepsy. Methods: We counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone (MCH) and histamine in 7 narcolepsy patients and 12 control subjects using stereological techniques. We identified histaminergic neurons using immunostaining for histidine decarboxylase (HDC). 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, while 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.

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 CSF histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in two mouse models of narcolepsy. Methods: We counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone (MCH) and histamine in 7 narcolepsy patients and 12 control subjects using stereological techniques. We identified histaminergic neurons using immunostaining for histidine decarboxylase (HDC). 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, while 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.

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35 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2013
Deposited On:19 Nov 2013 15:15
Last Modified:05 Apr 2016 17:10
Publisher:Wiley-Blackwell
ISSN:0364-5134
Publisher DOI:https://doi.org/10.1002/ana.24019
PubMed ID:24006291

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