Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: Evidence for the role of brain histamine in behavioral and sleep-wake control

Régis Parmentier, Hiroshi Ohtsu, Zahia Djebbara-Hannas, Jean Louis Valatx, Takehiko Watanabe, Jian Sheng Lin

Research output: Contribution to journalArticlepeer-review

372 Citations (Scopus)

Abstract

The hypothesis that histaminergic neurons are involved in brain arousal is supported by many studies. However, the effects of the selective long-term abolition of histaminergic neurons on the sleep-wake cycle, indispensable in determining their functions, remain unknown. We have compared brain histamine (HA)-immunoreactivity and the cortical-EEG and sleep-wake cycle under baseline conditions or after behavioral or pharmacological stimuli in wild-type (WT) and knock-out mice lacking the histidine decarboxylase gene (HDC-/-). HDC-/-mice showed an increase in paradoxical sleep, a decrease in cortical EEG power in θ-rhythm during waking (W), and a decreased EEG slow wave sleep/W power ratio. Although no major difference was noted in the daily amount of spontaneous W, HDC-/-mice showed a deficit of W at lights-off and signs of somnolence, as demonstrated by a decreased sleep latencies after various behavioral stimuli, e.g., WT-mice placed in a new environment remained highly awake for 2-3 hr, whereas HDC-/-mice fell asleep after a few minutes. These effects are likely to be attributable to lack of HDC and thus of HA. In WT mice, indeed, intraperitoneal injection of α-fluoromethylhistidine (HDC-inhibitor) caused a decrease in W, whereas injection of ciproxifan (HA-H3 receptor antagonist) elicited W. Both injections had no effect in HDC-/-mice. Moreover, PCR and immunohistochemistry confirmed the absence of the HDC gene and brain HAimmunoreactive neurons in the HDC-/-mice. These data indicate that disruption of HA-synthesis causes permanent changes in the cortical-EEG and sleep-wake cycle and that, at moments when high vigilance is required (lights off, environmental change...), mice lacking brain HA are unable to remain awake, a prerequisite condition for responding to behavioral and cognitive challenges. We suggest that histaminergic neurons also play a key role in maintaining the brain in an awake state faced with behavioral challenges.

Original languageEnglish
Pages (from-to)7695-7711
Number of pages17
JournalJournal of Neuroscience
Volume22
Issue number17
DOIs
Publication statusPublished - 2002 Sep 1

Keywords

  • Arousal
  • Behavioral challenge
  • Cortical EEG
  • Cortical activation
  • Histamine
  • Histaminergic neurons
  • Histidine decarboxylase knock-out mice
  • Sleep-wake cycle
  • Wakefulness

ASJC Scopus subject areas

  • Neuroscience(all)

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