GluN2B‐containing NMDA Receptors on Sst‐interneurons act as Initial Cellular Trigger for Antidepressant Actions of Ketamine

Ketamine's rapid antidepressant effects depend on GluN2B-containing NMDA receptors on somatostatin-expressing (Sst) interneurons in the medial prefrontal cortex (mPFC). In mice, a single subanesthetic dose of ketamine reduced NMDA-induced burst firing of Sst-interneurons, decreased inhibitory transmission, and increased excitatory transmission in layer V pyramidal neurons, reversing behavioral deficits caused by chronic unpredictable stress. These effects were absent in mice lacking GluN2B from Sst-interneurons. The findings identify Sst-interneurons as the initial cellular trigger for ketamine's synaptic and behavioral actions, supporting the disinhibition hypothesis whereby ketamine disinhibits pyramidal neurons via GluN2B-NMDARs on Sst-interneurons, activating mTOR signaling and enhancing synaptic function.

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Abstract

A single subanesthetic dose of ketamine exerts rapid antidepressant‐like effects via rapid glutamate efflux, activation of mTORC1 signaling, and enhanced synaptic transmission in the medial prefrontal cortex (mPFC); however, the initial cellular trigger for these synaptic and behavioral actions of ketamine still remains unclear. Here, we used electrophysiology, biochemistry, molecular biology and behavioral approaches to determine the baseline sex differences in behavior after GluN2B conditional deletion from Sst‐interneurons, and effect of ketamine on chronic unpredictable stress (CUS)‐induced behavioral deficits, activation of mTOR signaling cascade and changes in synaptic transmission in male and female GluN2B fl/fl (WT) and Sst‐cre GluN2Bfl/fl mice (KO) mice. Acute treatment of ketamine reduces NMDA‐induced burst firing of Sst‐interneurons ex vivo in mPFC. Deletion of GluN2B from Sst‐GABAergic interneurons in the KO produced sexually dimorphic changes in synaptic transmission and behavior. Consistent with the disinhibition hypothesis, ketamine reduces inhibitory, but enhances excitatory transmission of layer V pyramidal neurons of mPFC and reverses CUS‐induced behavioral deficits only in WT, but not KO, mice. Preliminary data demonstrate that deletion of GluN2B from Sst‐interneurons blocks ketamine‐induced activation of mTOR signaling cascade. Our results demonstrate that Sst‐interneurons are an initial cellular trigger for synaptic and behavioral actions of ketamine. Consistent with the disinhibition hypothesis, ketamine actions are mediated by GluN2B‐NMDARs on Sst‐interneurons via disinhibition of pyramidal neurons, activation of mTOR signaling, and enhanced synaptic function in mPFC.