Figure 4. Deletion of Wfs1 in the medial PFC is sufficient to cause stress-induced depression-related behavior.
(A) AAV2 expressing Cre recombinase tagged at the N-terminus with GFP (AAV2.CMV.HI.GFP-Cre.SV40) or control AAV2 expressing EGFP (AAV2.CMV.PI.EGFP.WPRE.bGH) was injected bilaterally in the medial PFC of Wfs1 F/F mice at P42 and allowed to express for 15 days. A subset of mice from both injected groups was subjected to 30 min ARS and 5 min short recovery followed by relevant behavioral assays. (B) Stereotaxic unilateral injection of AAV2.CMV.HI.GFP-Cre.SV40 in medial PFC demonstrates extremely high efficiency of the viral knockout strategy in deleting Wfs1 around site of injection. Compared with control vector injected mice which did not affect WFS expression, bilateral injection of AAV2.CMV.HI.GFP-Cre.SV40 results in loss of WFS1 in medial PFC (Wfs1/mPFC.KO) (C and D). (E) Under baseline conditions, Wfs1/mPFC.KO mice do not exhibit depression-related behaviors but following ARS, Wfs1/mPFC.KO mice exhibit a strong increase in episodes of immobility in Forced Swim Test (FST) (Two-way ANOVA—Bonferroni post hoc test: mPFC.KO Basal vs mPFC.KO + ARS, p < 0.01**, N = 8 per group). Wfs1/mPFC.KO mice also exhibit anhedonia following ARS in the sucrose preference test (SPT) (Two-way ANOVA—Bonferroni post hoc test: C + ARS vs mPFC.KO + ARS, p < 0.01**, N = 7 per group) (F). Wfs1/mPFC.KO mice have normal levels of spontaneous activity in the open field arena (G) and do not exhibit anxiety-related behavior in elevated plus maze as measured by percentage open arm entries (H).