In the visible platform

trial, nonenriched Bdnf+/− and Kif1a+/− mice showed performances comparable to nonenriched littermate control mice (littermate control versus Bdnf+/−: latency, F(1,22) = 0.01681, p = 0.8980; littermate control versus Kif1a+/−: latency, F(1,22) = 0.007734, p = 0.9307, DZNeP mouse two-way repeated-measures ANOVA) ( Figures S2P and S2W), and there were no significant differences between nonenriched and enriched mice (latency of nonenriched versus enriched: wild-type, F(1,22) = 0.3455, p = 0.5626; Bdnf+/−, F(1,22) = 0.1733, p = 0.6812; Kif1a+/−, F(1,22) = 1.461 × 10−14, p = 1.000, two-way repeated-measures ANOVA) ( Figures S2B, S2F, and S2J). Throughout the experiments, there were no significant differences in the average swim speed between nonenriched and enriched mice Tyrosine Kinase Inhibitor Library screening (nonenriched versus enriched [cm/s]: wild-type, 23.9 ± 1.0 versus 25.4 ± 0.9, p = 0.2959; Bdnf+/−, 25.1 ± 0.7 versus 25.3 ± 0.8, p = 0.8373; Kif1a+/−, 24.0 ± 1.0 versus 25.5 ± 0.9, p = 0.2622, two-tailed t test) ( Figures 2C, 2F, and 2I and Figures S2C, S2D, S2G, S2H, S2K, and S2L), and between genotypes (littermate control versus Bdnf+/− [cm/s]: 24.5 ± 0.8 versus 24.8 ± 0.8, p = 0.8605; littermate control versus Kif1a+/− [cm/s]: 24.6 ± 1.1 versus 23.9 ± 1.0, p = 0.6275, two-tailed t test) ( Figures S2Q–S2S and S2X–S2Z). We then examined the possible role

of KIF1A upregulation in nonspatial learning ability, using the contextual fear conditioning test. Exposure of wild-type mice to enrichment for 3 weeks significantly enhanced contextual freezing responses 24 hr after conditioning (nonenriched versus enriched: 33.5% ± 2.5% versus 51.7% ± 4.0%, p = 0.0013, two-tailed t test) (Figure 2K), Asenapine consistent with previous reports (Rampon et al., 2000a). Compared with nonenriched wild-type mice, nonenriched Bdnf+/−

mice exhibited impaired contextual fear learning (wild-type versus Bdnf+/−: 33.5% ± 2.5% versus 20.8% ± 1.8%, p < 0.01, post hoc Dunnett's test) ( Figure 2K), as previously reported ( Liu et al., 2004). Nonenriched Kif1a+/− mice showed intact contextual fear learning (wild-type versus Kif1a+/−: 33.5% ± 2.5% versus 30.8% ± 3.6%, p > 0.05, post hoc Dunnett’s test) ( Figure 2K). Significantly, in contrast to wild-type mice, no enhancement of contextual fear learning was found in enriched Bdnf+/− or Kif1a+/− mice, compared with respective nonenriched mice (nonenriched versus enriched: Bdnf+/−, 20.8% ± 1.8% versus 21.7% ± 1.5%, p = 0.7289; Kif1a+/−, 30.8% ± 3.6% versus 31.0% ± 3.7%, p = 0.9686, two-tailed t test) ( Figure 2K). There were no significant differences in freezing responses immediately after the foot shock between nonenriched and enriched mice (nonenriched versus enriched: wild-type, 14.8% ± 3.3% versus 16.7% ± 6.3%, p = 0.7921; Bdnf+/−, 14.6% ± 4.9% versus 12.5% ± 6.1%, p = 0.7942; Kif1a+/−, 14.6% ± 3.8% versus 10.4% ± 5.4%, p = 0.5373, two-tailed t test) ( Figure 2J).