A Schematic of the strategy of generating Wfs1 conditional knockout mice for Riluzole treatment. B Schematic of the forced swimming test. C Analysis of the immobility time during the forced swimming test in WT and CKO mice, n ≥ 12. D Analysis of the immobility time during the forced swimming test after Riluzole treatment in WT and CKO mice, n ≥ 11. E Schematic of the novel object test. F, G Quantification of the percentage of the number of contacts with #2 or novel object in WT and CKO mice during acquisition and recognition session, n ≥ 12. H, I Quantification of the percentage of the number of contacts with #2 or novel object in WT and CKO mice during acquisition and recognition session after Riluzole treatment, n ≥ 11. J Schematic of the water maze test. K Latency to find the platform in WT and CKO mice during 7-day training sessions, n ≥ 12. On the probe trial day, quantification of the latency to the original position of the platform (L), times of crossing the platform area (M) and the time spent in quadrant of the platform (N) in WT and CKO mice, n ≥ 12. O Latency to find the platform in WT and CKO mice during 7-day training sessions after Riluzole treatment, n ≥ 11. On the probe trial day, quantification of the latency to the original position of the platform (P), times of crossing the platform area (Q) and the time spent in quadrant of the platform (R) in WT and CKO mice after Riluzole treatment, n ≥ 11. S The working hypothesis underlying the autonomous effect by WFS1 deficiency in neurons and non-autonomous effect by astrocytic WFS1 deficiency. Data are presented as mean ± SD. p values calculated by unpaired two-tailed Student’s t test were *p < 0.05, **p < 0.01, and ***p < 0.001. Two-way ANOVA was used for analysis of latency during 7-day training sessions after Riluzole treatment in the water maze test, *p < 0.05, **p < 0.01, and ***p < 0.001 for comparison of WT and CKO mice, #p < 0.05 for comparison of the effect of Riluzole treatment.