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 4

AAV2GluN2BshRNA into the mPFC of SstCre+ mice produces sex differences in baseline behavior and blocks the antidepressant effects of ketamine.

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AAV2GluN2BshRNA into the mPFC of SstCre+ mice produces sex differences i...
(A) Procedure schematic. (B) Representative images of viral expression. Scale bars: 50 μm and 20 μm (insets). (C) GluN2B knockdown in SstCre+/AAV mice reduced baseline immobility (preswim) in males compared with sex-matched controls (n = 23 males, 20–22 females/group, males: t44 = 2.806, P = 0.0075), but did not affect time spent in center or distance traveled in the OFT (D and E; n = 21–22 males, 17–22 females/group). (F and I) Only WT-SstCre–/AAV-ket mice showed reduced immobility in the FST compared with controls: n = 10–12 (F) and 9–12 (I) per group (males — treatment: F1,40 = 9.248, P = 0.0041, genotype times treatment: F1,40 = 7.453, P = 0.0094; females — treatment: F1,38 = 6.567, P = 0.0145, genotype times treatment: F1,38 = 4.744, P = 0.0357). (G and J) Only WT-SstCre-/AAV-ket mice showed reduced latency to feed in the NSFT: n = 11–12 (G) and 9–12 (J) per group (males — treatment: F1,42 = 9.171, P = 0.0042, genotype times treatment: F1,42 = 7.716, P = 0.0081; females — treatment: F1,38 = 4.454, P = 0.0415, genotype times treatment: F1,38 = 6.176, P = 0.0175). (G and J) No differences were observed in home cage feeding. (H) Only male WT-SstCre–/AAV-ket mice showed increased time sniffing female urine in the FUST compared with controls (n = 11–12 per group, genotype: F1,84 = 102.6, P < 0.0001, treatment: F3,84 = 6.199, P = 0.0007, genotype times treatment: F3,84 = 5.065, P = 0.0028), with no differences in time sniffing water. (K and L) Representative traces of sIPSCs or sEPSCs in layer V pyramidal neurons. (K) SstCre+/AAV males had decreased sIPSCs and increased sEPSCs compared with controls (n = 25–36 cells, 8–9 mice) (L) SstCre+ females had decreased sIPSCs, but no differences on sEPSCs compared with controls (n = 12–19 cells, 5 mice). Behavioral data are represented as mean ± SEM. Preswim, OFT: unpaired 2-tailed t test. FST, NSFT: 2-way ANOVA with Tukey’s multiple-comparisons test. FUST: 2-way ANOVA with Sidak’s multiple-comparisons test. Electrophysiology data are represented as cumulative probability of the interevent interval (IEI). IEIs: Kolmogorov-Smirnov 2-sample test. *P < 0.05; **P < 0.01; ***P < 0.001. NS, nonsignificant.