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

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.

Histamine Increases Neuronal Excitability and Sensitivity of the Lateral Vestibular Nucleus and Promotes Motor Behaviors via HCN Channel Coupled to H2 Receptor

“…In the present study, by means of pharmacological manipulation to block HCN channels in the LVN, we find that rat motor performances on the rota-rod and balance beam remarkably decline (Figures 5A–D) and the improvement of motor performances induced by activation of histamine H2 receptors is significantly abolished (Figures 5E,F). These results, together with our previous findings that blockage of HCN channels in the cerebellar nuclei attenuates motor performances (Zhang et al, 2016), suggest that HCN channels coupled to histamine H2 receptors may mediate the modulation of the central histaminergic system on motor behaviors and play an important role in somatic motor control.…”

“…Several types of ionic channels/exchangers have been reported to be linked to histamine receptors and modulate the excitability of central vestibular nuclear neurons (Ris et al, 2001; Zhang et al, 2013, 2016; Yu et al, 2016). Here, we find that both the HCN channels and K + channels are involved in the excitation of LVN neurons induced by the activation of histamine H2 receptors.…”

“…Whole-cell patch-clamp recordings were performed as our previous report (Zhang et al, 2008, 2011, 2013, 2016; Yu et al, 2016). Briefly, recording pipettes (3–5 MΩ) were filled with an internal solution (140 mM K-methylsulfate, 7 mM KCl, 2 mM MgCl 2 , 10 mM HEPES, 0.1 mM EGTA, 4 mM Na 2 ATP, 0.4 mM GTP-Tris, adjusted to pH 7.25 with 1 M KOH).…”

“…The experimental procedures for immunostaining followed our previous reports (Zhang et al, 2011, 2013, 2016; Li et al, 2016). Rat (weighing 230–250 g) were deeply anesthetized with sodium pentobarbital and perfused transcardially with 100 ml of normal saline, followed by 450–500 ml of 4% paraformaldehyde in 0.1 M phosphate buffer.…”

“…The reduced locomotion is also observed in H3R-deficient mice (Toyota et al, 2002). Moreover, by means of pharmacological manipulation combining behavioral tests, our previous studies have demonstrated that histamine remarkably promotes motor balance and coordination on accelerating rota-rod and balance beam via activation of H2 receptors in the rat cerebellar fastigial and interposed nuclei (Song et al, 2006; He et al, 2012; Zhang et al, 2016). …”