Histamine N-methyltransferase regulates aggression and the sleep-wake cycle

Fumito Naganuma,Tadaho Nakamura,Anikó Kárpáti,Takuro Matsuzawa,Yamato Miura,Takeo Yoshikawa,Takatoshi Mochizuki,Asuka Mogi,Tomomitsu Iida,Nobuyuki Okamura,Kazuhiko Yanai,Atushi Yanai

doi:10.1038/s41598-017-16019-8

Fumito Naganuma, Tadaho Nakamura + Show 10 more

Open Access

https://doi.org/10.1038/s41598-017-16019-8

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Abstract

Histamine is a neurotransmitter that regulates diverse physiological functions including the sleep-wake cycle. Recent studies have reported that histaminergic dysfunction in the brain is associated with neuropsychiatric disorders. Histamine N-methyltransferase (HNMT) is an enzyme expressed in the central nervous system that specifically metabolises histamine; yet, the exact physiological roles of HNMT are unknown. Accordingly, we phenotyped Hnmt knockout mice (KO) to determine the relevance of HNMT to various brain functions. First, we showed that HNMT deficiency enhanced brain histamine concentrations, confirming a role for HNMT in histamine inactivation. Next, we performed comprehensive behavioural testing and determined that KO mice exhibited high aggressive behaviours in the resident-intruder and aggressive biting behaviour tests. High aggression in KO mice was suppressed by treatment with zolantidine, a histamine H2 receptor (H2R) antagonist, indicating that abnormal H2R activation promoted aggression in KO mice. A sleep analysis revealed that KO mice exhibited prolonged bouts of awakening during the light (inactive) period and compensatory sleep during the dark (active) period. Abnormal sleep behaviour was suppressed by treatment with pyrilamine, a H1R antagonist, prior to light period, suggesting that excessive H1R activation led to the dysregulation of sleep-wake cycles in KO mice. These observations inform the physiological roles of HNMT.

Highlights

Histamine is a neurotransmitter that regulates a variety of physiological functions including sleep-wake cycles, appetite, memory and the stress response[1,2,3,4]
knockout mice (KO) mice were indistinguishable from wild type mice (WT)
An H2 receptor (H2R) antagonist, significantly decreased the number of attacks by KO mice in the resident-intruder test, whereas pyrilamine, an H1R antagonist, had no effect (Fig. 3E). These results indicated that elevated histamine and H2R activation related to histamine N-methyltransferase (HNMT) deficiency drove aggressive behaviours in KO mice

Summary

Introduction

Histamine is a neurotransmitter that regulates a variety of physiological functions including sleep-wake cycles, appetite, memory and the stress response[1,2,3,4]. In vivo microdialysis revealed that KO mice had higher extracellular concentrations of histamine in the hypothalamic area, irrespective of light/dark cycles (Fig. 1C). We performed comprehensive behavioural testing to evaluate the behavioural effects of HNMT deficiency and elevated histamine in KO mice.

Results

Conclusion