GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions
Danielle M. Gerhard, … , Eric S. Wohleb, Ronald S. Duman
Danielle M. Gerhard, … , Eric S. Wohleb, Ronald S. Duman
Published November 19, 2019
Citation Information: J Clin Invest. 2020;130(3):1336-1349. https://doi.org/10.1172/JCI130808.
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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 5

Genetic deletion of Grin2b from Sst+ interneurons: behavioral and electrophysiological responses.

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Genetic deletion of Grin2b from Sst+ interneurons: behavioral and electr...
(A and B) Procedure schematics for baseline (A) and postketamine (B) behaviors. (C) Only SstCre+Grin2bfl male mice had reduced baseline immobility (preswim) when compared with sex-matched controls (SstCre–Grin2bfl; n = 8–10 males, 8–15 females/group, males: t16 = 2.421, P = 0.0277). (D and E) There were no effects in SstCre+Grin2bfl mice on baseline time spent in center or distance traveled in the OFT compared with sex-matched controls (n = 8–10 males, 8–15 females/ group). (F) Male SstCre+Grin2bfl mice showed significantly more time sniffing female urine compared with controls in the FUST (n = 7–9/group, test: F1,28 = 163.3, P < 0.0001, genotype: F1,28 = 7.244, P = 0.0119, test times genotype: F1,28 = 7.069, P = 0.0128). (G and H) In a naive group of male and female mice, only control SstCre-Grin2bfl-ket mice showed a significant reduction in (G) time spent immobile (n = 6–9/ group, genotype: F1,27 = 6.67, P = 0.02, treatment: F1,27 = 23.1, P < 0.0001, genotype times treatment: F1,27 = 29.5, P < 0.0001) and in (H) latency to feed in the novelty-suppressed feeding test (NSFT), when compared with controls (n = 6–9/group, treatment: F1,27 = 6.54, P = 0.02, treatment times genotype: F1,27 = 4.56, P = 0.04). No significant differences were observed in home cage feeding. (I) Brain slice electrophysiology schematic. (J) Representative traces of sIPSCs and sEPSCs. (K) Male SstCre+Grin2bfl mice had significantly decreased sIPSCs and increased sEPSCs compared with controls (n = 20–23 cells, 7–9 mice). (L) Female SstCre+Grin2bfl mice had both significantly decreased sIPSCs and sEPSCs compared with controls (n = 17–22 cells, 6–8 mice). Behavioral data are represented as mean ± SEM. Preswim and OFT: unpaired 2-tailed t test. FUST: 2-way ANOVA with Sidak’s multiple-comparisons test. FST and NSFT: 2-way ANOVA with Tukey’s multiple-comparisons test. Electrophysiology data are represented as the cumulative probability of the interevent interval (IEI). IEIs: Kolmogorov-Smirnov 2-sample test. *P < 0.05; **P < 0.01; ***P < 0.001. Abbreviations: sal, saline; ket, ketamine.