Anatomical, Physiological, and Pharmacological Characteristics of Histidine Decarboxylase Knock-Out Mice: Evidence for the Role of Brain Histamine in Behavioral and Sleep-Wake Control

• Published in: The Journal of neuroscience Vol. 22; no. 17; pp. 7695 - 7711
• Main Authors: Parmentier, Regis, Ohtsu, Hiroshi, Djebbara-Hannas, Zahia, Valatx, Jean-Louis, Watanabe, Takehiko, Lin, Jian-Sheng
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.09.2002; Society for Neuroscience
• Subjects: Animals; Behavior, Animal - drug effects; Behavior, Animal - physiology; Brain - metabolism; Circadian Rhythm - drug effects; Circadian Rhythm - physiology; Electrodes, Implanted; Electroencephalography - drug effects; Electromyography; Enzyme Inhibitors - pharmacology; Histamine - metabolism; Histamine H1 Antagonists - pharmacology; Histidine Decarboxylase - antagonists & inhibitors; Histidine Decarboxylase - deficiency; Histidine Decarboxylase - genetics; Imidazoles - pharmacology; Male; Methylhistidines - pharmacology; Mice; Mice, Knockout; Phenotype; Polymerase Chain Reaction; Reaction Time - drug effects; Reaction Time - physiology; Sleep, REM - drug effects; Sleep, REM - physiology; Theta Rhythm - drug effects; Wakefulness - drug effects; Wakefulness - physiology
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.22-17-07695.2002

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 theta-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 alpha-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 em leader ), 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.