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. 2018 Mar 1;8:3845. doi: 10.1038/s41598-018-22216-w

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Na_V1.6 knockout leads to empty nodes in myelinated fibers within the neuroma. (a) Confocal images showing Na_V1.6 or panNa_V (red) and contactin-associated protein (caspr, green) immunostaining as well as tdTomato signal (blue) in intact Tibial nerve (upper row) or neuroma (Common Peroneal nerve, bottom row) from AAV-GFP infected (WT control) and AAV-Cre infected (Na_V1.6^AAV KO) mice. Samples were collected 6 weeks after SNI and AAV injection. In intact nerve (aI) and neuroma (aIV) from wild-type mice, Na_V1.6 protein is present in every node of Ranvier (filled arrowhead). In intact nerve from Na_V1.6^AAV KO mice Na_V1.6 (aII) protein is stable in nodes (unfilled arrow head) along tdTomato positive fibers (blue, reporter for Na_V1.6 gene excision); similar nodal staining along tdTomato positive fibers is observed when a pan sodium channel antibody is used (aIII, unfilled arrow head). In neuroma from Na_V1.6^AAV KO mice (aV), Na_V1.6 protein is only present at nodes (filled arrow head) along tdTomato-negative fibers but absent at nodes along tdTomato-positive (blue) fibers (unfilled arrow head). Using a pan sodium channel antibody shows that the absence of Nav1.6 protein at nodes (unfilled arrow head) along tdTomato-positive (blue) fibers is not compensated by other Na_V isoforms (aVI). Filled arrow heads point to representative nodes along tdTomato-negative A-fibers and unfilled arrow heads point to representative nodes along tdTomato-positive A-fibers. Arrows point to representative non-myelinated regions within the neuroma where sodium channels accumulate following injury. Scale bar = 10 µm; Inset scale bar = 2 µm. (b) Comparison of average density of Na_V1.6-positive nodes in intact nerve (white, n = 10) and neuroma (grey, n = 10). (c) Comparison of average nodal gap length in intact nerve (white, n = 10) and neuroma (grey, n = 10). (d) Comparison of average nodal gap width in intact nerve (white, n = 10) and neuroma (grey, n = 10). (e) Percentage of Na_V1.6-positive neurons in neuroma after AAV-Cre (Na_V1.6^AAV KO, n = 5) treatment or AAV-GFP (WT control, n = 5) treatment. Data are presented as mean ± SEM. ***p < 0.001 based on unpaired t test.