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. 2018 Jan 24;9:347. doi: 10.1038/s41467-017-02729-0

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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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Fig. 6 — Mutant C9ORF72 MNs exhibit Ca²⁺-permeable AMPARs receptors and greater vulnerability to excitotoxicity. a Sample whole-cell voltage-clamp recordings conducted at −74 mV depicting the block of AMPA (10 μM)-mediated currents (in the presence of cyclothiazide (10 μM)) by Ca²⁺-permeable AMPAR-selective blocker NASPM (3 μM) in week 5 MNs derived from a control, mutant C9ORF72, or C9-Δ lines. Scale bars: 5 s, 50 pA. b Mean ( ± s.e.m.) percentage NASPM block of AMPA currents in all MNs examined at week 1, 3, and 5 (data for week 1/week 3/week 5; Con-1, n = 6/10/6, N = 3/3/1; Con-2, n = 14/12/6, N = 2/2/2; C9-1, n = 9/9/14, N = 2/1/3; C9-1Δ, n = 5/8/5, N = 2/2/2; C9-2, n = 9/12/12, N = 2/3/3; C9-2Δ, n = 8/10/10, N = 3/4/4; C9-3, n = 7/11/11, N = 3/3/3; C9-3Δ, n = 10/10/7, N = 3/3/3) after differentiation (statistical comparisons; one-way ANOVA with Bonferroni’s post hoc test). c Representative non-stationary fluctuation analysis recordings of AMPAR-mediated currents in the AC-current (upper) and DC-current modes (lower) of week 5 MNs derived from a control, mutant C9ORF72, or the C9-Δ lines. Current-variance plots (bottom right) generated from the recordings presented were used to derive the γ. Scale bars; 5 s, 40 pA. d Mean estimated AMPAR γ in all lines examined at week 1, 3, and 5 (data week 1/week 3/week 5; Con-1, n = 15/15/12, N = 4/4/3; Con-2, n = 13/15/8, N = 2/2/2; C9-1, n = 10/11/21, N = 2/3/3; C9-1Δ, n = 7/6/8, N = 2/2/2; C9-2, n = 15/15/13, N = 3/3/2; C9-2Δ, n = 11/12/7, N = 3/3/2; C9-3, n = 12/18/19, N = 4/3/4; C9-3Δ, n = 17/23/8, N = 4/4/2) after differentiation (statistical comparisons; one-way ANOVA with Bonferroni’s post hoc test). e Representative images of Calcein AM-stained neurons derived from control, C9, and C9-Δ lines before and after 24-h treatment of AMPA (100 μM) in the presence of cyclothiazide (100 µM). Scale bar: 50 µm. Cyclothiazide is an AMPAR-selective allosteric potentiator used to prevent rapid AMPAR desensitization. f Mean percentage cytotoxicity of MNs treated with AMPA, AMPA + JTX, and AMPA + CNQX (data represented as mean ± s.e.m., Con-1, N = 6; Con-2, N = 5; C9-1, N = 5; C9-1Δ, N = 5; C9-2, N = 9; C9-2Δ, N = 5; C9-3, N = 5; C9-3Δ, N = 5) and at least 100 cells per experiment, Greek letter phi denotes significant difference (two-way ANOVA with uncorrected Fisher's LSD) in cell death with JTX treatment when compared to AMPA treatment