Figure 3. Selective deletion of Wfs1 in cortical excitatory neurons precipitates stress-induced depression-related behaviors.
(A) Wfs1-mutant mice were generated by incorporating the conditional Wfs1-targeting vector that has the largest exon, exon 8, flanked by loxP sites. Wfs1 conditional KO (Wfs1/CKO) mice were produced by breeding Wfs1-mutant mouse bearing the Wfs1 conditional allele with Emx1.IRES.cre knock in mouse. (B) Normal pattern of WFS1 expression in the cerebral cortex (PFC, Ctx) and subcortical structures including striatum (Str), central amygdala (CeA), and hippocampus (CA1) is evident in wt (Wfs1 F/F) mice (top panel) whereas the cortical expression (cerebral cortex and hippocampus) of WFS1 is lost in Emx1.IRES.Cre Wfs1 F/F (Wfs1/CKO) mice. Wfs1 expression in CeA of Wfs1/CKO mouse brain is intact (bottom panel). (C) Wfs1/CKO mice exhibit equivalent episodes of immobility as WT mice in Porsolt's Forced Swim Test (FST) under baseline conditions but following acute restraint stress (ARS), they exhibit behavioral despair as indicated by increased episodes of immobility. FST: Two-way ANOVA—Bonferroni post hoc test: CKO Basal vs CKO + ARS, p < 0.05*, n = 8 per group. (D) Wfs1/CKO mice become anhedonic following ARS and lose normal preference for sucrose, but their total fluid intake is unchanged compared with WT regardless of exposure to stress (E). Sucrose preference test: Two-way ANOVA—Bonferroni post hoc test: CKO Basal vs CKO + ARS, p < 0.001**, n = 10 per group. Wfs1/CKO mice exhibit normal levels of spontaneous locomotion and acclimation to a novel arena in the open field test under baseline conditions and following ARS (F). Wfs1/CKO mice do not exhibit anxiety-related behavior following ARS as assayed by thigmotaxis in the open field arena (G). Likewise, the percentage time spent in open arms of the elevated plus maze is comparable for both genotypes (H). Wfs1/CKO mice display normal instrumental learning and reversal in three-choice operant chamber (I), and they display normal spatial learning and memory in Morris water maze in measures of swim distance, latency to reach platform, and % time spent in the probe quadrant NE post training (J).