Hcn1 is a tremorgenic genetic component in a rat model of essential tremor.

Yukihiro Ohno,Takuji Imaoku,Tadao Serikawa,Takashi Kuramoto,Masashi Sasa,Saki Shimizu,Ayaka Tatara,Takahiro Ishii

doi:10.1371/journal.pone.0123529

Yukihiro Ohno, Takuji Imaoku + Show 6 more

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https://doi.org/10.1371/journal.pone.0123529

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Abstract

Genetic factors are thought to play a major role in the etiology of essential tremor (ET); however, few genetic changes that induce ET have been identified to date. In the present study, to find genes responsible for the development of ET, we employed a rat model system consisting of a tremulous mutant strain, TRM/Kyo (TRM), and its substrain TRMR/Kyo (TRMR). The TRM rat is homozygous for the tremor (tm) mutation and shows spontaneous tremors resembling human ET. The TRMR rat also carries a homozygous tm mutation but shows no tremor, leading us to hypothesize that TRM rats carry one or more genes implicated in the development of ET in addition to the tm mutation. We used a positional cloning approach and found a missense mutation (c. 1061 C>T, p. A354V) in the hyperpolarization-activated cyclic nucleotide-gated 1 channel (Hcn1) gene. The A354V HCN1 failed to conduct hyperpolarization-activated currents in vitro, implicating it as a loss-of-function mutation. Blocking HCN1 channels with ZD7288 in vivo evoked kinetic tremors in nontremulous TRMR rats. We also found neuronal activation of the inferior olive (IO) in both ZD7288-treated TRMR and non-treated TRM rats and a reduced incidence of tremor in the IO-lesioned TRM rats, suggesting a critical role of the IO in tremorgenesis. A rat strain carrying the A354V mutation alone on a genetic background identical to that of the TRM rats showed no tremor. Together, these data indicate that body tremors emerge when the two mutant loci, tm and Hcn1A354V, are combined in a rat model of ET. In this model, HCN1 channels play an important role in the tremorgenesis of ET. We propose that oligogenic, most probably digenic, inheritance is responsible for the genetic heterogeneity of ET.

Highlights

Essential tremor (ET) is one of the most common movement disorders
To determine whether HCN1 channel dysfunction is responsible for the generation of tremors in vivo, we evaluated the actions of a selective HCN1 channel blocker, ZD7288, in doi:10.1371/journal.pone.0123529.g003
A marked and significant elevation in Fos expression was observed in the inferior olive (IO) (P = 0.0495), compared with the TRMR rats given vehicle alone (Fig 5). These findings indicate that inhibition of HCN1 channels by ZD7288 causes excitation of IO neurons concomitantly with the generation of tremors

Summary

Introduction

Essential tremor (ET) is one of the most common movement disorders. The major manifestation of ET is a postural and/or kinetic (action) tremor, which predominantly affects the hands, head, and vocal organs at a frequency of 4–12 Hz [1]. A recent meta-analysis using populationbased studies estimated a pooled prevalence of ET (at all ages) of 0.9% [2]. Hcn Mutation in a Rat Model of Essential Tremor research, few advances have been achieved in our understanding of the etiology of ET. Certain environmental factors may be at least partly involved in nonfamilial forms of ET [3]. A family history of ET and higher concordance rates in monozygotic than dizygotic twins support a major role for genetic factors in the development of ET [4]

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