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Cover ArticleResearch Articles, Systems/Circuits

Studying Independent Kcna6 Knock-out Mice Reveals Toxicity of Exogenous LacZ to Central Nociceptor Terminals and Differential Effects of Kv1.6 on Acute and Neuropathic Pain Sensation

Liam J. Peck, Ryan Patel, Paula Diaz, Yolanda M. Wintle, Anthony H. Dickenson, Andrew J. Todd, Margarita Calvo and David L.H. Bennett
Journal of Neuroscience 3 November 2021, 41 (44) 9141-9162; https://doi.org/10.1523/JNEUROSCI.0187-21.2021
Liam J. Peck
1Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, United Kingdom
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Ryan Patel
2Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom
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Paula Diaz
3Departamento de Fisiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile and Millennium Nucleus for the Study of Pain, Santiago, 8330025, Chile
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Yolanda M. Wintle
1Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, United Kingdom
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Anthony H. Dickenson
2Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom
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Andrew J. Todd
4Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, G12 8QQ, United Kingdom
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Margarita Calvo
3Departamento de Fisiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile and Millennium Nucleus for the Study of Pain, Santiago, 8330025, Chile
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David L.H. Bennett
1Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, United Kingdom
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Abstract

The potassium channel Kv1.6 has recently been implicated as a major modulatory channel subunit expressed in primary nociceptors. Furthermore, its expression at juxtaparanodes of myelinated primary afferents is induced following traumatic nerve injury as part of an endogenous mechanism to reduce hyperexcitability and pain-related hypersensitivity. In this study, we compared two mouse models of constitutive Kv1.6 knock-out (KO) achieved by different methods: traditional gene trap via homologous recombination and CRISPR-mediated excision. Both Kv1.6 KO mouse lines exhibited an unexpected reduction in sensitivity to noxious heat stimuli, to differing extents: the Kv1.6 mice produced via gene trap had a far more significant hyposensitivity. These mice (Kcna6lacZ) expressed the bacterial reporter enzyme LacZ in place of Kv1.6 as a result of the gene trap mechanism, and we found that their central primary afferent presynaptic terminals developed a striking neurodegenerative phenotype involving accumulation of lipid species, development of “meganeurites,” and impaired transmission to dorsal horn wide dynamic range neurons. The anatomic defects were absent in CRISPR-mediated Kv1.6 KO mice (Kcna6−/−) but were present in a third mouse model expressing exogenous LacZ in nociceptors under the control of a Nav1.8-promoted Cre recombinase. LacZ reporter enzymes are thus intrinsically neurotoxic to sensory neurons and may induce pathologic defects in transgenic mice, which has confounding implications for the interpretation of gene KOs using lacZ. Nonetheless, in Kcna6−/− mice not affected by LacZ, we demonstrated a significant role for Kv1.6 regulating acute noxious thermal sensitivity, and both mechanical and thermal pain-related hypersensitivity after nerve injury.

SIGNIFICANCE STATEMENT In recent decades, the expansion of technologies to experimentally manipulate the rodent genome has contributed significantly to the field of neuroscience. While introduction of enzymatic or fluorescent reporter proteins to label neuronal populations is now commonplace, often potential toxicity effects are not fully considered. We show a role of Kv1.6 in acute and neuropathic pain states through analysis of two mouse models lacking Kv1.6 potassium channels: one with additional expression of LacZ and one without. We show that LacZ reporter enzymes induce unintended defects in sensory neurons, with an impact on behavioral data outcomes. To summarize we highlight the importance of Kv1.6 in recovery of normal sensory function following nerve injury, and careful interpretation of data from LacZ reporter models.

  • gangliosides
  • Kv1.6
  • LacZ
  • neuropathic pain
  • nociception
  • pain

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The Journal of Neuroscience: 41 (44)
Journal of Neuroscience
Vol. 41, Issue 44
3 Nov 2021
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Studying Independent Kcna6 Knock-out Mice Reveals Toxicity of Exogenous LacZ to Central Nociceptor Terminals and Differential Effects of Kv1.6 on Acute and Neuropathic Pain Sensation
Liam J. Peck, Ryan Patel, Paula Diaz, Yolanda M. Wintle, Anthony H. Dickenson, Andrew J. Todd, Margarita Calvo, David L.H. Bennett
Journal of Neuroscience 3 November 2021, 41 (44) 9141-9162; DOI: 10.1523/JNEUROSCI.0187-21.2021

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Studying Independent Kcna6 Knock-out Mice Reveals Toxicity of Exogenous LacZ to Central Nociceptor Terminals and Differential Effects of Kv1.6 on Acute and Neuropathic Pain Sensation
Liam J. Peck, Ryan Patel, Paula Diaz, Yolanda M. Wintle, Anthony H. Dickenson, Andrew J. Todd, Margarita Calvo, David L.H. Bennett
Journal of Neuroscience 3 November 2021, 41 (44) 9141-9162; DOI: 10.1523/JNEUROSCI.0187-21.2021
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Keywords

  • gangliosides
  • Kv1.6
  • LacZ
  • neuropathic pain
  • nociception
  • pain

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