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.

Role of Corticotropin-Releasing Factor in Cerebellar Motor Control and Ataxia

“…Lentivirus (LV)-Crf-RNAi treatment significantly shortened stride lengths (n = 10; left stride length: p < 0.001; right stride length: p < 0.001) and lengthened stride width (n = 10, p < 0.05) ( Figure 1D). We also applied rota-rod and balance beam tests [19][20][21] to examine the effect of downregulation of Crf mRNA in the IO on motor coordination and balance. Rats treated with LV-Crf-RNAi displayed a remarkable decrease in the time spent on the accelerating rota-rod (n = 10, p < 0.001) ( Figure 1E) and a prolonged time traversing the balance beam (n = 11, p < 0.001) ( Figure 1F).…”

“…All behavioral trainings/tests started at the same time (10:00 a.m.) each day. In order to achieve a stable motor performance on the rota-rod and balance beam, each animal was trained daily for at least 10 trials for 3 to 5 consecutive days before test as we previously reported [19][20][21].…”

“…The test was performed to assess motor coordination and balance of rodents [21,58]. Each rat was placed in an individual compartment of the rota-rod treadmill (Model 7750, Ugo Basile, Varese, Italy) and was required to keep walking to avoid falling off the device.…”

“…We also used a balance beam test to assess motor balance and coordination of rats [21,58]. The balance beam was a rod with length of 160 cm and diameter of 2.5 cm.…”

The Role of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in the Pathophysiology of Absence Epilepsy

“…[32] The HCN isoforms at axon terminals have been shown to regulate vesicle release, such as regulating gamma-Aminobutyric acid(GABA) release pre-synaptically [33] and glutamate release through voltage-gated T-type calcium (Ca[V]3.2) channels. [34] The coupling of HCN channels to other proteins, such as histamine H2 receptors [35] and Atype potassium channels, has also been shown to regulate neuronal excitability. [36] In summary, I(h) in the soma and proximal dendrites functions to depolarize and stabilize the resting membrane potential, and in distal dendrites, it decreases dendritic integration and limits dendritic calcium spikes.…”