Increase of histaminergic tuberomammillary neurons in narcolepsy

Authors

  • Philipp O. Valko MD,

    1. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
    2. Department of Neurology, University Hospital of Zurich, Zurich, Switzerland
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  • Yury V. Gavrilov MD, PhD,

    1. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
    2. Department of Neurology, University Hospital of Zurich, Zurich, Switzerland
    3. Department of General Pathology and Pathological Physiology, Institute of Experimental Medicine, St Petersburg, Russia
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  • Mihoko Yamamoto MS,

    1. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
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  • Hasini Reddy MD, DPhil,

    1. Department of Neuropathology, Beth Israel Deaconess Medical Center, Boston, MA
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  • Johannes Haybaeck MD, PhD,

    1. Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria
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  • Emmanuel Mignot MD, PhD,

    1. Department of Psychiatry, Stanford University Center for Narcolepsy, Palo Alto, CA
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  • Christian R. Baumann MD,

    1. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
    2. Department of Neurology, University Hospital of Zurich, Zurich, Switzerland
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  • Thomas E. Scammell MD

    Corresponding author
    1. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
    • Address correspondence to Dr Scammell, Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: tscammel@bidmc.harvard.edu

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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.

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

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