These behavioral data suggest that the cognitive impairment by repeated stress may be due to the Nedd4-1 and Proteases inhibitor Fbx2-dependent loss of glutamate receptors in PFC. To understand the

potential mechanism underlying the region specificity of the effects of repeated stress on glutamate receptor expression and function, we examined the level of Nedd4-1 and Fbx2 in PFC, striatum, and hippocampus from control versus stressed young male rats. As shown in Figure 8E, the level of Nedd4-1 was significantly higher in PFC or striatum than in hippocampus from control animals (p < 0.01, n = 8). After repeated stress, Nedd4-1 was significantly elevated in PFC (∼70% increase, p < 0.01, n = 6 pairs) but was significantly reduced in striatum (∼35% decrease, p < 0.01, n = 7 pairs) and unchanged in hippocampus (p > 0.05, n = 8 pairs). Moreover, the level of Fbx2 was significantly

higher in PFC than in striatum or hippocampus from control or stressed animals (Figure 8F, p < 0.01, n = 7 pairs). These results provide a potential reason for the higher sensitivity of PFC to repeated stress than other brain regions, like Lapatinib supplier the striatum and hippocampus. In the present study, we have identified glutamate receptors as an important molecular substrate of repeated stress. Given the significance of glutamatergic signaling in PFC-mediated cognitive processes (Goldman-Rakic, 1995 and Lisman et al., 1998), it is not surprising that repeated stress impairs the object recognition memory, which is reminiscent of the memory deficits following bilateral infusion of glutamate receptor antagonists directly into PFC. The loss of PFC glutamatergic responses could also underlie the stress-induced other behavioral impairments found earlier (Liston

et al., 2006, Cerqueira et al., 2005 and Cerqueira et al., 2007). Mounting evidence has suggested that stress induces divergent changes in different brain regions (de Kloet et al., 2005 and McEwen, 2007). Chronic stress causes atrophy of dendrites in the CA3 region, suppresses neurogenesis of dentate gyrus granule neurons, and impairs hippocampal-dependent cognitive functions (McEwen, 1999 and Joëls unless et al., 2007). High levels of corticosterone or chronic stress also impair long-term potentiation (LTP) and facilitate long-term depression (LTD) induced by electrical stimulation in hippocampus (Kim and Diamond, 2002 and Alfarez et al., 2003). On the other hand, chronic stress has been shown to enhance amygdala-dependent fear conditioning (Conrad et al., 1999) and anxiety-like behavior (Mitra et al., 2005), which may be correlated to the stress-induced dendritic growth and spinogenesis in this region (Vyas et al., 2002 and Mitra et al., 2005). In this study, we have demonstrated that glutamatergic transmission in PFC pyramidal neurons is significantly suppressed in young male rats exposed to repeated stress, without the apparent loss of synapses.