Ketamine reverses chronic stress-induced behavioral changes via the expression of Ca ²⁺ -permeable AMPA receptors in mice

Chronic 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 Ca ²⁺ -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. Here, we use whole-cell patch-clamp recordings from CA1 pyramidal neurons in female and male hippocampal slices to affirm that subanesthetic low-dose ketamine treatment induces CP-AMPAR expression in these cells. Using 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, hippocampus-dependent fear memory loss, 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. From this, our findings suggest that subanesthetic low-dose ketamine rapidly triggers the expression of CP-AMPARs in the hippocampus, which induces antidepressant and antistress effects.