Fig. 7: Selective Gsto2 knockdown rescues the dopaminergic dysfunction and its consequences.

a–c, Representative images from the SNc and d–f VTA brain regions immunostained with TH from Trkb^Penk-WT control (a,d), mutant Gsto2-shRNA (b,e) or scrambled shRNA (c,f). g, Scatter–bar plots showing fold change of TH⁺ cell counts in SNc–VTA (significant difference between mutant scrambled shRNA and control mice, adj **P = 0.0029; significant difference between mutant scrambled shRNA and mutant Gsto2-shRNA, adj *P = 0.032; no difference between mutant Gsto2-shRNA and controls, adj P = 0.126 (n = 3 each genotype, male mice). h, Scatter–bar plots showing analysis of TH⁺ cells in the SNc–VTA region of mutant Gsto2-shRNA or scrambled injected at 3 months and analysed at 8 months (TH⁺ cell numbers is similar to control mice). i–k, Representative striatal images of SST⁺ and l–n, NPY⁺ immunofluorescence from Trkb^Penk-WT control (i,l), Trkb^Penk-KO mutants injected at 3 months with Gsto2-shRNA (j,m) or scrambled shRNA (k,n) in the striatum and analysed 3 weeks later (age 15 W). o, Scatter–bar plots showing a significant decrease of striatal immunoreactive SST⁺ and NPY⁺ cells in mutants injected with scrambled shRNA vs control mice, adj ***P = 0.0004 and **P = 0.0052, respectively, a significant difference between mutant scrambled shRNA and mutant Gsto2-shRNA, adj **P = 0.0043 and *P = 0.017, respectively; no difference between mutant Gsto2-shRNA and control for NPY, adj P = 0.5 and an adj *P = 0.046 for SST (n = 3 each genotype, male mice). p–r, Representative striatal images of immunofluorescence for SST from Trkb^Penk-WT control (p), Trkb^Penk-KO mutant injected at 3 months with Gsto2-shRNA (q) or scrambled shRNA (r) in the striatum and analysed at 8 months. s, Scatter–bar plots showing a significant fold change decrease of striatal immunoreactive SST⁺ and NPY⁺ cells in mutant scrambled shRNA vs controls, adj ***P = 0.0003 and adjusted *P = 0.017, respectively; a significant difference between mutant scrambled shRNA and mutant Gsto2-shRNA, adj ***P = 0.0007 and adjusted *P = 0.046, respectively; no difference between mutant Gsto2-shRNA and control (SST, adjusted *P = 0.36 and NPY, adjusted P = 0.7) (n = 3 each genotype, male mice). t, Scatter–bar plot showing the oxygen flux for different respiratory states evaluated as per (Fig. 4e–g). Significant differences are indicated by asterisks and are detailed in Table S3 (TrkB^Penk-WT, n = 6; TrkB^Penk-KO Gsto2-shRNA, n = 5; and TrkB^Penk-KO scrambled shRNA, n = 4; male mice). u, Cartoon summary illustrating the consequences of Trkb deletion in striatal iSPNs. Values are means; error bars, s.e.m. P statistic in g, o and s from one-way ANOVA, followed by Tukey’s multiple comparison analysis; in t, from two-way ANOVA and Tukey’s multiple comparisons tests. Scale bars in a, d, i, m and q, 50 μm. This figure was partially created with BioRender.com (basic section showing the striatum in u).

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