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. 2022 Jul 15;13:4114. doi: 10.1038/s41467-022-31817-z

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© The Author(s) 2022

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. 1 — a MCI protocol at pH 7.2 with 100 μM memantine (left; Glu = glutamate; Mem = memantine); overlay of I_Control and I_MCI (middle; I_MCI in red); point-by-point ratio, I_MCI/I_Control (right). Similar current trace formatting is used in following figures. b Charged and uncharged memantine; amount uncharged at pH 6.3, 7.2, and 9.0. c MCI protocol with 100 μM memantine, pH of all solutions = 9.0. d Min I_MCI/I_control with 100 μM memantine, pH of all solutions = 7.2 or 9.0 (pH 7.2, 0.611 ± 0.046, n = 4; pH 9.0, 0.139 ± 0.007, n = 4) compared with two-sided t-test (t = 8.76, df = 6, p = 0.0001). e pH 9.0 jump protocol with 100 μM memantine. f pH 6.3 jump protocol with 100 μM memantine. g [Memantine]-MCI curves at pH 6.3 (jump protocol), 7.2, and 9.0 (jump protocol). Only two memantine concentrations were used at pH 6.3 (see text). Min I_MCI/I_Control values at 10 μM memantine (pH 7.2, n = 4; pH 9.0, n = 4) compared with two-sided t-test (t = 6.94, df = 6, p = 0.0004). Min I_MCI/I_Control values at 30 μM memantine (pH 7.2, n = 4; pH 9.0, n = 9) compared with two-sided t-test (t = 9.00, df = 11, p = 2.1*10^-6). Min I_MCI/I_Control values at 100 μM memantine (pH 6.0, n = 5; pH 7.2, n = 4; pH 9.0, n = 4) compared with one-way ANOVA (F(2, 10) = 65.1, p = 1.9*10^-6) and Tukey post-hoc test (pH 6.3 vs 7.2, p = 0.00071; pH 6.3 vs 9.0, p = 1.3*10^-6; pH 7.2 vs 9.0, p = 0.00060). Min I_MCI/I_Control values at 300 μM memantine (pH 6.0, n = 4; pH 7.2, n = 4; pH 9.0, n = 4) compared with one-way ANOVA (F(2, 9) = 51.2, p = 1.2*10^-5) and Tukey post-hoc test (pH 6.3 vs 7.2, p = 0.0082; pH 6.3 vs 9.0, p = 9.2*10^-6; pH 7.2 vs 9.0, p = 0.00048). In a, c, e, f, color of lines above traces indicates solution pH (blue, pH 6.3; black, pH 7.2; magenta, pH 9.0; same color coding used in following figures). h Memantine MCI IC₅₀s (pH 6.3 jump, 841 ± 5 μM, n = 5; pH 7.2, 71.0 ± 1.7 μM, n = 4; pH 9.0 jump, 8.77 ± 3.26 μM, n = 12) compared with one-way ANOVA (F(2,18) = 1.23*10⁴, p < 1*10^-15) and Tukey post-hoc test (pH 6.3 vs 7.2, p = 2.7*10^-14; pH 6.3 vs 9.0, p = 2.7*10^-14; pH 7.2 vs 9.0, p = 1.0*10^-8). All figures: *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001. In d, g, h, mean ± SEM is plotted. In all figure legends, n is the number of biologically independent cells.