Fig 2: Prolonged pharmacological blockade of GAT1 activity recapitulates the scaling up of corticostriatal excitatory synaptic transmission as that seen in the GAT1-/- mice(A–C) Effects of chronic GAT1 blockade on PPRs of eEPSCs at the corticostriatal pathway. (A) Experimental scheme. (B) Representative traces showing paired-pulse responses with 50-ms interval. (C) Statistics of PPRs. Unpaired Student’s t test, Vehicle group, n = 14 neurons from eight mice; NO-711 group, n = 14 neurons from eight mice.(D–G) Effects of GAT1 blockade on AMPAR (D and E) and NMDAR (F and G)-mediated synaptic currents. (D and F) Representative traces. (E) I-O relationship of AMPAR-mediated currents. Unpaired Student’s t test and two-way repeated measures ANOVA, main effects of NO-711, F1,189 = 40.483, p < 0.001, Vehicle group, n = 13 neurons from seven mice; NO-711 group, n = 17 neurons from eight mice. (G) I-O relationship of NMDAR-mediated currents. Two-way repeated measures ANOVA, main effects of NO-711, F1,126 = 0.115, p = 0.735, Vehicle group, n = 10 neurons from five mice; NO-711 group, n = 8 neurons from five mice.(H and I) Effects of chronic GAT1 blockade on AMPAR/NMDAR ratios. Unpaired Student’s t test, Vehicle group, n = 10 neurons from three mice; NO-711 group, n = 12 neurons from three mice.Data are represented as mean ± SEM. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, no significant significance.

Fig 3: Characterization of striatal inhibitory and excitatory synaptic transmission in the GAT1-/- mice(A and B) Decay time of electrical stimulation-evoked inhibitory postsynaptic currents (eIPSCs) of MSNs in dorsal striatum. (A) Representative eIPSC traces. (B) Quantification of decay time of 1-pulse and 4-pulse (100 Hz) compound eIPSCs before and after bath application of NO-711 (10 µM). GAT1+/+ versus GAT1-/-, unpaired Student’s t test; GAT1+/+ versus GAT1+/+ + NO-711, GAT1-/- versus GAT1-/- + NO-711, paired Student’s t test, n = 10 neurons from four GAT1+/+ mice and n = 9 neurons from three GAT1-/- mice.(C and D) Tonic GABA currents. Unpaired Student’s t test, n = 9 neurons from four GAT1+/+ mice and n = 9 neurons from five GAT1-/- mice.(E–I) Miniature inhibitory postsynaptic currents. Unpaired Student’s t test, n = 11 neurons from three GAT1+/+ mice and n = 9 neurons from four GAT1-/- mice.(J–L) PPRs at the corticostriatal projections. (J) Experimental schemes. Ctx, cortex; LV, lateral ventricle; CPu, caudate putamen (dorsal striatum). (K) Representative traces showing paired-pulse responses with 50-ms interval. (L) Statistics of PPRs. Unpaired Student’s t test, n = 14 neurons from six GAT1+/+ mice and n = 17 neurons from five GAT1-/- mice.(M-P) AMPAR (M and N) and NMDAR (O and P)-mediated synaptic currents evoked by electrical stimuli of different intensities at the corticostriatal projections. (M and O) Representative traces. (N) I-O relationship of AMPAR-mediated currents. Unpaired Student’s t test and two-way repeated measures ANOVA, main effects of genotype, F1,161 = 25.802, p < 0.001, n = 12 neurons from three GAT1+/+ mice and n = 11 neurons from three GAT1-/- mice. (P) I-O relationship of NMDAR-mediated currents. Two-way repeated measures ANOVA, main effects of genotype, F1,134 = 3.618, p = 0.06, n = 11 neurons from three GAT1+/+ mice and n = 8 neurons from three GAT1-/- mice.(Q and R) AMPAR/NMDAR ratios at the corticostriatal synapses. Unpaired Student’s t test, n = 6 neurons from two GAT1+/+ mice and n = 7 neurons from two GAT1-/- mice.Data are represented as mean ± SEM. *, p < 0.05, **, p < 0.01, ***, p < 0.001, NS, no significant significance.