Stress affects brain functions, which leads to the development of mental disorders like anxiety, depression, cognitive decline, and social dysfunction. There is increasing focus on the role of nutritional, herbal and nutraceutical compounds on mental and cognitive functioning. Interestingly, studies suggest that American ginseng (Panax quinquefolius L.) extracts (G1899) improve cognition. We thus examined whether G1899 showed protective effects on stress-induced behavioral changes in animals. 200 mg/kg G1899 was orally administered daily for 4 weeks to 2-3-month-old female and male mice before inducing stress. To induce acute stress in animals, we intraperitoneally injected a low dose of lipopolysaccharides (LPS) (10 μg/kg), and saline was used as a control. We also used chronic restraint stress (CRS) as a chronic stress model in mice. After LPS injection or CRS, multiple behavioral assays were carried out – a sucrose preference test, an open filed test, reciprocal social interaction, contextual fear conditioning, and a tail suspension test – to determine whether acute or chronic stress affected animals’ behaviors and whether G1899 had protective effects against stress-induced behavioral dysfunction. We found that both LPS injection and CRS induced stress-related behavioral dysfunction, including depression-like behavior, anhedonia, social dysfunction, and fear memory impairments in both females and males. However, G1899 treatment was sufficient to reverse stress-induced behavioral abnormalities in animals. Our data further suggested that G1899 reduced the activity of hippocampal neurons by suppressing glutamatergic activity. Our study suggests that G1899 supplements can be protective against both acute and chronic stress in mice by suppressing neuronal and synaptic activity.
Resource LinkKetamine is shown to enhance excitatory synaptic drive in multiple brain areas, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamine’s therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that reduces excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment in cultured mouse hippocampal neurons significantly reduces Ca2+ and calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately leads to the expression of Ca2+-Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). The ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and glutamate receptor plasticity in cultured hippocampal neurons. Moreover, when a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within 1 hr after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamine’s effects on animals’ behaviors. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity, which in turn enhances synaptic strength to induce rapid antidepressant actions.
Resource LinkChronic stress affects brain functions, leading to the development of mental disorders like anxiety and depression, as well as cognitive decline and social dysfunction. Among many biological changes in chronically stressed brains, disruptions in AMPA Receptor (AMPAR)-mediated synaptic transmission in the hippocampus are associated with stress responses. We have revealed that low-dose ketamine rapidly induces the expression of GluA1-containing, GluA2-lacking Ca2+-Permeable AMPARs (CP-AMPARs), which enhances glutamatergic synaptic strength in hippocampal neurons. Additionally, subanesthetic low-dose ketamine decreases anxiety- and depression-like behaviors in naïve animals. In addition to reducing depression, some research indicates that ketamine may have protective effects against chronic stress in both humans and animals. However, the role of CP-AMPARs in the actions of ketamine's antistress effects is largely unknown. We use whole-cell patch-clamp recordings from CA1 pyramidal neurons in female and male hippocampal slices and multiple behavioral assays, including reciprocal social interaction, contextual fear conditioning, and tail suspension test. We demonstrate that low-dose ketamine treatment reverses chronic restraint stress (CRS)-induced social dysfunction, a loss of hippocampus-dependent fear learning and memory, and depression-like behavior in both female and male mice. Furthermore, we show that the ketamine-induced antistress effects on these behaviors are dependent on CP-AMPAR expression. Our findings suggest that subanesthetic low-dose ketamine rapidly triggers the expression of CP-AMPARs in the hippocampus, which induces antidepressant and antistress effects.
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