The loss of hypothalamic neurons that produce wake-promoting
orexin (
hypocretin)
neuropeptides is responsible for
narcolepsy type 1 (NT1). While the number of
histamine neurons is increased in patients with NT1, results on
orexin-deficient mouse models of NT1 are inconsistent. On the other hand, the effect of
histamine deficiency on
orexin neuron number has never been tested on mammals, even though
histamine has been reported to be essential for the development of a functional
orexin system in zebrafish. The aim of this study was to test whether
histamine neurons are increased in number in
orexin-deficient mice and whether
orexin neurons are decreased in number in
histamine-deficient mice. The hypothalamic neurons expressing
L-histidine decarboxylase (HDC), the
histamine synthesis
enzyme, and those expressing
orexin A were counted in four
orexin knock-out mice, four
histamine-deficient HDC knock-out mice, and four wild-type C57BL/6J mice. The number of HDC-positive neurons was significantly higher in
orexin knock-out than in wild-type mice (2,502 ± 77 vs. 1,800 ± 213, respectively, one-tailed t-test, P = 0.011). Conversely, the number of
orexin neurons was not significantly lower in HDC knock-out than in wild-type mice (2,306 ± 56 vs. 2,320 ± 120, respectively, one-tailed t-test, P = 0.459). These data support the view that
orexin peptide deficiency is sufficient to increase
histamine neuron number, supporting the involvement of the
histamine waking system in the pathophysiology of NT1. Conversely, these data do not support a significant role of
histamine in
orexin neuron development in mammals.