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Selective Modulation of Histaminergic Inputs on Projection Neurons of Cerebellum Rapidly Promotes Motor Coordination via HCN Channels

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Abstract

Insights into function of central histaminergic system, a general modulator originating from the hypothalamus for whole brain activity, in motor control are critical for understanding the mechanism underlying somatic-nonsomatic integration. Here, we show a novel selective role of histamine in the cerebellar nuclei, the final integrative center and output of the cerebellum. Histamine depolarizes projection neurons but not interneurons in the cerebellar nuclei via the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to histamine H2 receptors, which are exclusively expressed on glutamatergic and glycinergic projection neurons. Furthermore, blockage of HCN channels to block endogenous histaminergic afferent inputs in the cerebellar nuclei significantly attenuates motor balance and coordination. Therefore, through directly and quickly modulation on projection neurons but not interneurons in the cerebellar nuclei, central histaminergic system may act as a critical biasing force to not only promptly regulate ongoing movement but also realize a rapid integration of somatic and nonsomatic response.

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Acknowledgments

We thank Dr Rob Leurs (VU University Amsterdam, Amsterdam, the Netherlands) for his generous gifts of histamine H4 receptor agonist and antagonist. The work was supported by grants 31070959, 31071021, 31171050, 31330033, 91332124, 31471112 and NSFC/RGC Joint Research Scheme 31461163001 from the National Natural Science Foundation of China; SRFDP/RGC ERG grant 20130091140003 and NCET Program from the State Educational Ministry of China; grants BK2011014 and BK20140599 from the Natural Science Foundation of Jiangsu Province, China; and grant 2013T60520 from the China Postdoctoral Science Foundation.

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    Authors and Affiliations

    1. State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University, Mailbox 426, 22 Hankou Road, Nanjing, 210093, China

      Jun Zhang, Qian-Xing Zhuang, Bin Li, Guan-Yi Wu, Jing-Ning Zhu & Jian-Jun Wang

    2. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China

      Wing-Ho Yung

    3. Department of Physiology, Third Military Medical University, Chongqing, 400038, China

      Jun Zhang

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    1. Jun Zhang
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    Correspondence to Jing-Ning Zhu or Jian-Jun Wang.

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    Jun Zhang, Qian-Xing Zhuang and Bin Li contributed equally to this work.

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    Zhang, J., Zhuang, QX., Li, B. et al. Selective Modulation of Histaminergic Inputs on Projection Neurons of Cerebellum Rapidly Promotes Motor Coordination via HCN Channels. Mol Neurobiol 53, 1386–1401 (2016). https://doi.org/10.1007/s12035-015-9096-3

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