Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors

Summary & key facts

Researchers tested how ketamine produces fast antidepressant effects in brain cells and in mice. They found that a low dose of ketamine quickly changes the kinds of glutamate receptors at connections between neurons, boosting signals in a way that can reduce anxiety- and depression-like behavior in mice within about an hour. These results point to a specific chain of changes inside cells, but the work was done in mouse brain tissue and live mice, so it does not prove the same process happens in people.

Key facts:

• The team studied both mouse brain cells grown in the lab and live mice to see what ketamine does to neurons and behavior.
• In lab-grown mouse hippocampal neurons, ketamine reduced calcium signals and the activity of a protein called calcineurin. This led to more phosphorylation (a chemical change) of the GluA1 part of AMPA-type glutamate receptors.
• Because of that chemical change, neurons started to show more calcium-permeable AMPA receptors. These are AMPA receptors that lack the GluA2 part and let calcium flow into the cell more easily.
• In live mice, a low, non-anesthetic dose of ketamine increased levels of GluA1 at synapses in the hippocampus within about one hour, but did not increase GluA2 levels.
• The low dose of ketamine quickly reduced anxiety-like behavior in an open-field test and reduced depression-like behavior in a tail-suspension test in both male and female mice.
• When researchers gave mice a drug that blocks the calcium-permeable AMPA receptors, ketamine no longer produced the behavioral benefits. This shows those special AMPA receptors are needed for the ketamine effect in mice.

Abstract

Ketamine 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 Ca 2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that reduces excitatory synaptic transmission and postsynaptic Ca 2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca 2+ 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 Ca 2+ and calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately leads to the expression of Ca 2+ -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.

Topics

Neuroscience and Neuropharmacology Research Treatment of Major Depression Tryptophan and brain disorders

Categories

Health Sciences Medicine Pharmacology

Tags

AMPA receptor Antidepressant Biology Glutamate receptor Hippocampus Internal medicine Ketamine Medicine Neuroscience Pharmacology Receptor

Substances

Ketamine

Conditions & symptoms

Anxiety Depression Anxiety or worry Sadness or low mood