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

Background and Purpose

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.

Experimental Approach

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.

Key Results

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-AMPARs.

Conclusion and Implications

Our findings suggest that subanesthetic low-dose ketamine rapidly triggers synaptic insertion of CP-AMPARs in the hippocampus, which induces antidepressant and antistress effects.

What is already known

• After demonstrating rapid and robust antidepressant efficacy, the US Food and Drug Administration (FDA) approved esketamine (the S enantiomer form of ketamine) for the treatment of depression in 2019, sparking a surge in clinical and public interest around the world.

• Although the exact mechanisms are largely unknown, one mechanism postulated for ketamine’s actions involves the enhancement of excitatory synaptic drive through an increase in AMPA receptor (AMPAR)-mediated synaptic activity.

What this study adds

• This study discovers that a single dose of ketamine rapidly (∼one hour) induces synaptic insertion of GluA1-containing, GluA2-lacking C a ²⁺ - P ermeable AMPAR s (CP-AMPARs), which is required for the antistress effects in animals.

Clinical significance

• Ketamine is typically given in just a single dose or short series of doses rather than repeated treatments because of potential misuse and addictive properties. Furthermore, rapid relapse of depression occurs after cessation of ketamine treatment (18 - 19 days post-infusion).

• Understanding the precise mechanisms behind ketamine’s antidepressant effects could lead to the development of new clinical approaches to overcome its primary therapeutic limitation of restricted patient use.

• Unfortunately, the potential sex differences in response to ketamine have been particularly understudied at this time although the hypersensitivity of females to ketamine’s effects at lower doses has been shown in several animals’ studies. Therefore, our findings may help develop tailored treatment and dosing in clinics.