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. 2024 Jan 24;27(3):433–448. doi: 10.1038/s41593-023-01558-3

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© The Author(s) 2024

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. 3 — a, Lactate FRET sensor (Laconic) expression in optic nerve axons through intravitreal AAV delivery in wild-type mice. Color-coded ratio images in ACSF with 10 mM glucose, additional 20 mM lactate (Lac), and after glucose and lactate removal. hCMV, human cytomegalovirus; mTFP, monomeric teal fluorescent protein. b, Ratio quantification of conditions in a, confirming the sensor’s response to lactate availability (n = 4 mice; [glucose]/[lactate] in mM: 10/0 versus 10/20: **P = 0.0052; 10/0 versus 0/0: **P = 0.0014; 10/20 versus 0/0: ***P < 0.0001; one-way ANOVA Holm–Šídák’s multiple-comparison test). c, Lactate level changes (%) upon 10-Hz (n = 8 mice), 25-Hz (n = 8 mice) or 50-Hz (n = 15 mice) stimulation. d, Lactate surges (initial slopes), showing higher lactate increases at higher frequencies (50 Hz, n = 15 mice; 25 Hz, n = 8 mice; 10 Hz, n = 8 mice; 50 versus 25 Hz, *P = 0.0141; 50 versus 10 Hz, ***P < 0.0001; 25 versus 10 Hz, *P = 0.0141; one-way ANOVA with Holm–Šídák’s multiple-comparison test). e,f, Ba²⁺ (100 μM) reduced the 50-Hz-induced axonal lactate increase (e) by 34 ± 11% (f) (n = 7, two-sided paired t test, *P = 0.0249). wt, wild type. g, OL-specific Kir4.1 cKO (Kir4.1^fl/fl;MOGiCre) and control (ctrl) mice (Kir4.1^fl/fl). h–m, Axonal lactate and CAP analyses in ∼3-month-old cKO (n = 16) and control (n = 8) mice. h, Time course of axonal lactate levels during 50-Hz stimulation and GD. Traces were normalized to the minimum level after GD. i, Basal axonal lactate levels were lower in cKO versus control (*P = 0.0119, two-sided unpaired t test). j, 50-Hz-evoked lactate surge was lower in cKO (*P = 0.0174, two-sided unpaired t test). k, Lactate decline rate during GD was similar between genotypes (P = 0.1318, two-sided unpaired t test). l, CAP decline kinetics during GD were comparable between genotypes (CAP decline slope: P = 0.7934, time to 50% CAP area: P = 0.7265, two-sided unpaired t test). m, Normalized (Norm.) axonal lactate and CAP time traces during GD in control (left) and cKO (middle) mice. Right, graph showing that the temporal delay between 50% lactate decline and CAP drop (dashed arrows in left and middle) was similar between genotypes (P = 0.9789, two-sided unpaired t test). Data are represented as mean ± s.e.m.