title: Histamine Increases Neuronal Excitability and Sensitivity of the Lateral Vestibular Nucleus and Promotes Motor Behaviors via HCN Channel Coupled to H2 Receptor.
abstract: Histamine and histamine receptors in the central nervous system actively participate in the modulation of motor control. In clinic, histamine-related agents have traditionally been used to treat vestibular disorders. Immunohistochemical studies have revealed a distribution of histaminergic afferents in the brainstem vestibular nuclei, including the lateral vestibular nucleus (LVN), which is critical for adjustment of muscle tone and vestibular reflexes. However, the mechanisms underlying the effect of histamine on LVN neurons and the role of histamine and histaminergic afferents in the LVN in motor control are still largely unknown. Here, we show that histamine, in cellular and molecular levels, elicits the LVN neurons of rats an excitatory response, which is co-mediated by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and K+channels linked to H2 receptors. Blockage of HCN channels coupled to H2 receptors decreases LVN neuronal sensitivity and changes their dynamic properties. Furthermore, in behavioral level, microinjection of histamine into bilateral LVNs significantly promotes motor performances of rats on both accelerating rota-rod and balance beam. This promotion is mimicked by selective H2 receptor agonist dimaprit, and blocked by selective H2 receptor antagonist ranitidine. More importantly, blockage of HCN channels to suppress endogenous histaminergic inputs in the LVN considerably attenuates motor balance and coordination, indicating a promotion role of hypothalamo-vestibular histaminergic circuit in motor control. All these results demonstrate that histamine H2 receptors and their coupled HCN channels mediate the histamine-induced increase in excitability and sensitivity of LVN neurons and contribute to the histaminergic improvement of the LVN-related motor behaviors. The findings suggest that histamine and the histaminergic afferents may directly modulate LVN neurons and play a critical role in the central vestibular-mediated motor reflexes and behaviors.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University Nanjing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University Nanjing, China.
authors.forename: Xiao-Yang
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing UniversityNanjing, China; Department of Medicine, Huaibei Vocational and Technical CollegeHuaibei, China.
authors.forename: Ai-Hong
authors.initials: AH
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University Nanjing, China.
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University Nanjing, China.
authors.forename: Zhang-Peng
authors.initials: ZP
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University Nanjing, China.
authors.forename: Jia-Yuan
authors.initials: JY
authors.lastname: Zhou
authors.affiliation: Department of Physiology, LKS Faculty of Medicine, The University of Hong Kong Hong Kong, Hong Kong.
authors.forename: Ying-Shing
authors.initials: YS
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University Nanjing, China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University Nanjing, China.
authors.forename: Jing-Ning
authors.initials: JN
authors.lastname: Zhu
keywords: HCN channel; histamine; histamine H2 receptor; lateral vestibular nucleus; motor control