In contrast, CRF2-deficient mice showed increased depression-like behaviors (Bale and Vale, 2003; Todorovic et al., 2009), and this effect may be due to elevated hippocampal CRF1 receptor activity caused by MEK/ERK pathway activation in the absence of CRF2 (Todorovic et al., 2009). This evidence concerns the gene CRHR2 and major depressive disorder.