Low-dose ketamine rapidly induces the expression of calcium-permeable AMPA receptors (CP-AMPARs) in the hippocampus, which enhances glutamatergic synaptic strength. In mice subjected to chronic restraint stress, low-dose ketamine reverses social dysfunction, loss of hippocampus-dependent fear learning and memory, and depression-like behavior in both females and males. These antistress effects depend on CP-AMPAR expression. The findings suggest that subanesthetic low-dose ketamine triggers CP-AMPAR expression in the hippocampus, producing antidepressant and antistress effects.
Chronic stress disrupts AMPA receptor signaling in the hippocampus, contributing to anxiety, depression, and cognitive decline. Low-dose ketamine rapidly increases GluA1-containing, GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs) in hippocampal neurons, enhancing glutamatergic synaptic strength and reducing anxiety- and depression-like behaviors in naïve animals. Ketamine may also protect against chronic stress effects, but whether CP-AMPARs mediate its antistress actions remains unknown.