HYPERPOLARIZATION-ACTIVATED CURRENT /H IN MOUSE TRIGEMINAL SENSORY NEURONS IN A TRANSGENIC MOUSE MODEL OF FAMILIAL HEMIPLEGIC MIGRAINE TYPE-1

被引:6
作者
Eroli, Francesca [1 ]
Vilotti, Sandra [1 ]
van den Maagdenberg, Arn M. J. M. [2 ,3 ]
Nistri, Andrea [1 ]
机构
[1] Int Sch Adv Studies SISSA, Neurosci Dept, Trieste, Italy
[2] Leiden Univ, Dept Neurol, Med Ctr, Leiden, Netherlands
[3] Univ Med Ctr, Dept Human Genet, Leiden, Netherlands
关键词
trigeminal ganglion; excitability; P2X3; ZD7288; CGRP; HCN; ROOT GANGLION NEURONS; CURRENT I-H; GENE-RELATED PEPTIDE; CHANNEL SURFACE EXPRESSION; GATED CATION CHANNELS; HCN2 ION CHANNELS; PACEMAKER CHANNELS; SPREADING DEPRESSION; UP-REGULATION; RECEPTOR;
D O I
10.1016/j.neuroscience.2017.03.033
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Transgenic knock-in (KI) mice that express Ca(v)2.1 channels containing an R192Q gain-of-function mutation in the alpha(1A) subunit known to cause familial hemiplegic migraine type-1 in patients, exhibit key disease characteristics and provide a useful tool to investigate pathophysiological mechanisms of pain transduction. Previously, KI trigeminal sensory neurons were shown to exhibit constitutive hyper excitability due to up-regulation of ATP-gated P2X3 receptors that trigger spike activity at a more negative threshold. This implies that intrinsic neuronal conductances may shape action potential generation in response to ATP, which could act as a mediator of migraine headache. Here we investigated whether the hyperpolarization-activated conductance /(h), mediated by hyperpolarization activated cyclic nucleotide gated channels (HCN), contributes to sub-threshold behavior and firing in wild-type (WT) and KI trigeminal ganglia (TG) neurons. Whereas most WT and KI trigeminal neurons expressed /(h) current, blocked by the specific inhibitor ZD7288, it was smaller in KI neurons despite similar activation and deactivation kinetics. HCN1 and HCN2 were the most abundantly expressed subunits in TG, both in situ and in culture. In KI TG neurons, HCN2 subunits were predominantly present in the cytoplasm, not at the plasma membrane, likely accounting for the smaller it, of such cells. ZD7288 hyperpolarized the membrane potential, thereby raising the firing threshold, and prolonging the spike trajectory to generate fewer spikes due to P2X3 receptor activation. The low amplitude of /(h) in KI TG neurons suggests that down-regulation of ih current in sub-threshold behavior acts as a compensatory mechanism to limit sensory hyper excitability, manifested under certain stressful stimuli. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码:47 / 64
页数:18
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