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Hyperpolarization-activated current Ih in mouse trigeminal sensory neurons in a transgenic mouse model of familial hemiplegic migraine type-1.
Neuroscience 2017; 351:47-64N

Abstract

Transgenic knock-in (KI) mice that express CaV2.1 channels containing an R192Q gain-of-function mutation in the α1A 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 hyperexcitability 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 Ih, 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 Ih 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 Ih 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 Ih in KI TG neurons suggests that down-regulation of Ih current in sub-threshold behavior acts as a compensatory mechanism to limit sensory hyperexcitability, manifested under certain stressful stimuli.

Authors+Show Affiliations

Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy. Electronic address: feroli@sissa.it.Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy. Electronic address: vilotti@sissa.it.Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands; Department of Human Genetics, University Medical Centre, Leiden, Netherlands. Electronic address: A.M.J.M.van_den_Maagdenberg@lumc.nl.Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy. Electronic address: nistri@sissa.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28363781

Citation

Eroli, Francesca, et al. "Hyperpolarization-activated Current Ih in Mouse Trigeminal Sensory Neurons in a Transgenic Mouse Model of Familial Hemiplegic Migraine Type-1." Neuroscience, vol. 351, 2017, pp. 47-64.
Eroli F, Vilotti S, van den Maagdenberg AMJM, et al. Hyperpolarization-activated current Ih in mouse trigeminal sensory neurons in a transgenic mouse model of familial hemiplegic migraine type-1. Neuroscience. 2017;351:47-64.
Eroli, F., Vilotti, S., van den Maagdenberg, A. M. J. M., & Nistri, A. (2017). Hyperpolarization-activated current Ih in mouse trigeminal sensory neurons in a transgenic mouse model of familial hemiplegic migraine type-1. Neuroscience, 351, pp. 47-64. doi:10.1016/j.neuroscience.2017.03.033.
Eroli F, et al. Hyperpolarization-activated Current Ih in Mouse Trigeminal Sensory Neurons in a Transgenic Mouse Model of Familial Hemiplegic Migraine Type-1. Neuroscience. 2017 05 20;351:47-64. PubMed PMID: 28363781.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hyperpolarization-activated current Ih in mouse trigeminal sensory neurons in a transgenic mouse model of familial hemiplegic migraine type-1. AU - Eroli,Francesca, AU - Vilotti,Sandra, AU - van den Maagdenberg,Arn M J M, AU - Nistri,Andrea, Y1 - 2017/03/29/ PY - 2016/11/24/received PY - 2017/03/15/revised PY - 2017/03/20/accepted PY - 2017/4/2/pubmed PY - 2018/2/9/medline PY - 2017/4/2/entrez KW - CGRP KW - HCN KW - P2X3 KW - ZD7288 KW - excitability KW - trigeminal ganglion SP - 47 EP - 64 JF - Neuroscience JO - Neuroscience VL - 351 N2 - Transgenic knock-in (KI) mice that express CaV2.1 channels containing an R192Q gain-of-function mutation in the α1A 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 hyperexcitability 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 Ih, 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 Ih 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 Ih 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 Ih in KI TG neurons suggests that down-regulation of Ih current in sub-threshold behavior acts as a compensatory mechanism to limit sensory hyperexcitability, manifested under certain stressful stimuli. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/28363781/Hyperpolarization_activated_current_Ih_in_mouse_trigeminal_sensory_neurons_in_a_transgenic_mouse_model_of_familial_hemiplegic_migraine_type_1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(17)30199-9 DB - PRIME DP - Unbound Medicine ER -