The specific loss of Wfs1 in the forebrain of Wfs1/CKO mice presented an important opportunity to determine whether the enhanced sensitivity to stress and depression of patients with Wolfram syndrome (Koido et al., 2005; Swift and Swift, 2005), or the behavioral abnormalities of Wfs1 KO mice (Kato et al., 2008; Luuk et al., 2009), might result from abnormal function of forebrain neurons. Here, WFS1 is linked to major depressive disorder.