The occurrence of major depressive disorder (MDD) has been linked to an increased vulnerability to stress. The basolateral amygdala (BLA) is one of the critical brain areas that involved in the regulation of pathological reactivity to stress. Increasing evidence indicates that the EphB2 receptor (EphB2) plays a critical role in neuropsychiatric disorders, such as Alzheimer's disease, pain and anxiety. However, whether the EphB2 in the BLA is involved in stress vulnerability is unclear. Here, we identified EphB2 in the BLA as a key regulator contributed to the modulation of stress vulnerability in adult mice. We found that the expression of EphB2 in the BLA was significantly increased in the animal model induced by chronic social stress. Knockdown of EphB2 in the BLA produced antidepressant-like behavioral effects, whereas activation of EphB2 in the BLA increased the susceptibility to subthreshold social defeat stress. Furthermore, we demonstrated that the role of EphB2 in the stress vulnerability was mediated by modulating NMDA receptors, since the knockdown of EphB2 in the BLA prevented not only the increase in the amplitudes of both the miniature and the evoked NMDAR-mediated EPSC, but also the enhancement of surface expression of NMDARs in the defeated mice. Taken together, these results suggest that EphB2 in the BLA is a critical factor contributes to the vulnerability to stress, which may be a potential target for the treatment of depression.

Acute ethanol intoxication by excessive drinking is an important cause of alcohol-induced death. Stress exposure has been identified as one risk factor for alcohol abuse. Previous reports indicated that stressors may augment inhibitory effects of alcohol, but the underlying mechanism remains unknown. Here, we reported that chronic unpredictable stress increased the sensitivity to the acute ethanol intoxication in mice via impairing nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-catalase signaling. Nrf2 activity regulates the expression of catalase, a key antioxidant enzyme that mediates ethanol oxidation in the brain. Pharmacological blockade of catalase or Nrf2 activity significantly aggravated acute ethanol intoxication. Sulforaphane, a cruciferous vegetable-derived activator of Nrf2, significantly attenuated acute ethanol intoxication. Furthermore, the stress-induced aggravation of acute alcoholism was rapidly reversed by sulforaphane. Our findings suggest that Nrf2 may function as a novel drug target for the prevention of acute alcoholism, especially in psychiatric patients, by controlling catalase-mediated ethanol oxidation.

Aquaporin-4 (AQP-4) is the predominant water channel in the brain and primarily expressed in astrocytes. Astrocytes have been generally believed to play important roles in regulating synaptic plasticity and information processing. A growing number of evidence shows that AQP-4 plays a potential role in the regulation of astrocyte function. However, little is known about the function of AQP-4 for synaptic plasticity in the hippocampus. Therefore, we evaluated long-term depression (LTD) in the hippocampus and the extinction of fear memory of AQP-4 knockout (KO) and wild-type (WT) mice. We found that AQP-4 deficiency facilitated fear memory extinction and NMDA receptors (NMDARs)-dependent LTD in the CA3-CA1 pathway. Furthermore, AQP-4 deficiency selectively increased GluN2B-NMDAR-mediated excitatory postsynaptic currents (EPSCs). The excessive activation of extrasynaptic GluN2B-NMDAR contributed to the facilitation of NMDAR-dependent LTD and enhancement of fear memory extinction in AQP-4 KO mice. Thus, it appears that AQP-4 may be a potential target for intervention in fear memory extinction. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.