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The Journal of Neuroscience, September 1, 2002, 22(17):7695-7711

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 Parmentier¹, Hiroshi Ohtsu², Zahia Djebbara-Hannas¹, Jean-Louis Valatx¹, Takehiko Watanabe², and Jian-Sheng Lin¹

¹ Institut National de la Santé et de la Recherche Médicale U480, Department of Experimental Medicine, Faculty of Medicine, Claude Bernard University, 69373 Lyon, France, and ² Department of Cellular Pharmacology, Tohoku University, School of Medicine, Aoba-ku, Sendai 980-8575, Japan

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 -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 -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 HA-immunoreactive 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.

Key words: wakefulness; sleep-wake cycle; cortical activation; arousal; histaminergic neurons; histamine; histidine decarboxylase knock-out mice; cortical EEG; behavioral challenge

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22177695-17$05.00/0

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