GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions
Danielle M. Gerhard, Santosh Pothula, Rong-Jian Liu, Min Wu, Xiao-Yuan Li, Matthew J. Girgenti, Seth R. Taylor, Catharine H. Duman, Eric Delpire, Marina Picciotto, Eric S. Wohleb, Ronald S. Duman
Danielle M. Gerhard, Santosh Pothula, Rong-Jian Liu, Min Wu, Xiao-Yuan Li, Matthew J. Girgenti, Seth R. Taylor, Catharine H. Duman, Eric Delpire, Marina Picciotto, Eric S. Wohleb, Ronald S. Duman
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Research Article Neuroscience

GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

Abstract

A single subanesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates this increase and ketamine’s behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell-specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrated that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gad1) interneurons, as well as subtypes expressing somatostatin (Sst) or parvalbumin (Pvalb), but not glutamate principle neurons in the medial prefrontal cortex (mPFC). Further analysis of GABA subtypes showed that cell-specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.

Authors

Danielle M. Gerhard, Santosh Pothula, Rong-Jian Liu, Min Wu, Xiao-Yuan Li, Matthew J. Girgenti, Seth R. Taylor, Catharine H. Duman, Eric Delpire, Marina Picciotto, Eric S. Wohleb, Ronald S. Duman

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Figure 6

Infusion of AAV2GluN2BshRNA into the mPFC of PvalbCre+ male and female mice blocks the antidepressant effects of ketamine.

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Infusion of AAV2GluN2BshRNA into the mPFC of PvalbCre+ male and female m...
(A) Procedure schematic. (B) Representative images of virus-mediated expression and recombination in the mPFC of WT-PvalbCre–/AAV and PvalbCre+/AAV mice. Scale bars: 50 μm and 20 μm (insets). (C) GluN2B knockdown in PvalbCre+/AAV mice had no effect on baseline immobility (preswim; n = 19–24 males and 14–21 females per group). (D and E) GluN2B knockdown in PvalbCre+/AAV mice had no effect on baseline time spent in center or distance traveled in the open field test (OFT); however, there was a strong trend toward reduced distance traveled in PvalbCre+/AAV females (n = 18–23 males and 14–20 females per group). (F and H) Only WT-PvalbCre–/AAV-ket mice showed significantly reduced immobility in the forced swim test (FST) compared with their saline controls for male (F) and female (H) mice; however, PvalbCre+/AAV-sal female mice showed a significant reduction in immobility compared with WT-PvalbCre–/AAV-sal females: n = 9–12 (F) and 8–11 (H) per group; males — genotype times treatment: F1,39 = 5.1, P = 0.0291; females — genotype times treatment: F1,30 = 9.094, P = 0.0052. (G and I) Only WT-PvalbCre–/AAV-ket mice showed significantly reduced latency to feed in the novelty-suppressed feeding test (NSFT) compared with controls for (G) males and (I) females: n = 9–13 (G) and 6–11 (I) per group; males — treatment: F1,37 = 10.91, P = 0.0021; females — genotype: F1,30 = 7.782, P = 0.0091, treatment: F1,30 = 4.926, P = 0.0342. All data are represented as mean ± SEM. Preswim and OFT: unpaired 2-tailed t tests performed within sex. FST and NSFT: 2-way ANOVA with Tukey’s multiple-comparisons test. *P < 0.05; **P < 0.01.