Contribution of astrocytic histamine N-methyltransferase to histamine clearance and brain function in mice
Contribution of astrocytic histamine N-methyltransferase to histamine clearance and brain function in mice
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DOI：
10.1016/j.neuropharm.2022.109065
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发表时间：
2022-04
影响因子：
4.7
通讯作者：
R. Otsuka;Fumito Naganuma;Tadaho Nakamura;H. Miwa;Rumi Nakayama-Naono;T. Matsuzawa;Yurika Komatsu;Yuki Sato;Yuna Takahashi;Haruna Tatsuoka-Kitano;Kazuhiko Yanai;T. Yoshikawa
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文献类型：
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作者：
R. Otsuka;Fumito Naganuma;Tadaho Nakamura;H. Miwa;Rumi Nakayama-Naono;T. Matsuzawa;Yurika Komatsu;Yuki Sato;Yuna Takahashi;Haruna Tatsuoka-Kitano;Kazuhiko Yanai;T. Yoshikawa
脑组织胺作为一种神经递质参与脑内各种活动的调节。以往的研究表明，组胺N-甲基转移酶（HNMT），组胺代谢酶，控制脑组胺浓度和脑功能。然而，星形胶质细胞或神经元HNMT的组胺能系统的调节的相对贡献仍然是不确定的。在这里，我们表型星形胶质细胞特异性HNMT基因敲除（cKO）小鼠，以澄清参与星形胶质细胞HNMT组胺清除和脑function.First，我们进行了组织学检查，使用HNMT报告小鼠，并显示了广泛的HNMT分布在大脑和星形胶质细胞HNMT表达。然后，我们通过Cre-loxP系统建立了cKO小鼠，并证实cKO原代星形胶质细胞中HNMT的表达显著降低。尽管对照组和cKO组大脑皮质中的总HNMT水平无显著差异，但cKO皮质中组胺释放后的组胺浓度升高。在行为测试中，在cKO小鼠中观察到运动协调受损和运动活性降低。然而，焦虑样行为，抑郁样行为和记忆功能没有改变星形胶质细胞HNMT中断。虽然睡眠分析表明觉醒和睡眠的数量没有变化，但觉醒期间δ频率的功率密度增加表明cKO小鼠的皮质激活较低。这些结果表明，星形胶质细胞HNMT有助于组胺释放后，在皮质中的组胺清除，并在运动协调，自发活动和警觉状态的调节中发挥作用。
Brain histamine acts as a neurotransmitter in the regulation of various brain activities. Previous studies have shown that histamineN-methyltransferase (HNMT), a histamine-metabolizing enzyme, controls brain histamine concentration and brain function. However, the relative contribution of astrocytic or neuronal HNMT to the regulation of the histaminergic system is still inconclusive. Here, we phenotyped astrocytes-specificHNMTknockout (cKO) mice to clarify the involvement of astrocytic HNMT in histamine clearance and brain function.First, we performed histological examinations using HNMT reporter mice and showed a wide distribution of HNMT in the brain and astrocytic HNMT expression. Then, we created cKO mice by Cre-loxP system and confirmed thatHNMTexpression in cKO primary astrocytes was robustly decreased. Although total HNMT level in the cortex was not substantially different between control and cKO brains, histamine concentration after histamine release was elevated in cKO cortex. In behavioral tests, impaired motor coordination and lower locomotor activity were observed in the cKO mice. However, anxiety-like behaviors, depression-like behaviors, and memory functions were not altered by astrocytic HNMT disruption. Although sleep analysis demonstrated that the quantity of wakefulness and sleep did not change, the increased power density of delta frequency during wakefulness indicated lower cortical activation in cKO mice. These results demonstrate that astrocytic HNMT contributes to histamine clearance after histamine release in the cortex and plays a role in the regulation of motor coordination, locomotor activity, and vigilance state.