Bidirectional control of vesicular GABA release, LTP, and amotivation by GluN2D-selective allosteric modulators and ketamine.
Viktor J Oláh, Isabelle F Witteveen, Tue G Banke, Alexa M Leahy, Ryan Keable, Riley E Perszyk, Cara T Khayat, TrangKimberly T Nguyen, Brianna J Bixler, Frances G Ghinger, Detlef Vullhorst, Yeeun Yook, Scott J Myers, Elijah Z. Ullman, Jing Zhang, Hao Xing, John F Traynelis, Eva S Diaz, Sukhan Kim, Sophia Boraschi, Nicholas S Akins, Ken H Liu, Alet van der Westhuyzen, Yanli Yang, Chad R Camp, Andres Buonanno, Randy A Hall, James Q Zheng, Dennis C Liotta, Matthew J Kennedy, Katherine W Roche, Shannon L Gourley, Hongjie Yuan, Matthew J M Rowan, Stephen F Traynelis
Cell Reports July 24, 2026 DOI: 10.1016/j.celrep.2026.117707 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic science study in mice (preclinical) Peer reviewed |
|---|---|
| Population | Mice, including mice lacking GluN2D in parvalbumin interneurons |
| Interventions | Subanesthetic ketamine NAB14 |
| Topics | Depression Ketamine Esketamine |
| Keywords | Cp Glun2d Nmdar Interneuron Presynaptic |
| Key points | GluN2D-NMDARs are presynaptic on hippocampal parvalbumin interneurons and bidirectionally control GABA release via basal glutamate. In mice lacking interneuron GluN2D, GABA release was not inhibited by GluN2C/D modulators or subanesthetic ketamine, suggesting GluN2D-dependent presynaptic regulation may underlie some ketamine effects. The GluN2C/D inhibitor NAB14 reproduced ketamine's durable LTP enhancement and reward-motivation recovery in a depression model without ketamine's undesirable effects. |
Abstract
GABAergic inhibitory interneurons balance brain activity by suppressing excessive excitatory signaling and shaping network oscillations. Despite this critical function, our understanding of how neural circuits regulate GABAergic systems remains limited. Although N-methyl-D-aspartate receptor (NMDAR) functionality is defined by the GluN2A-D subunits, the interneuron NMDAR subunit composition remains unknown. Here, we show that GluN2D-NMDARs reside at presynaptic terminals of hippocampal parvalbumin-interneurons, and that the GluN2D intracellular C-terminal contains presynaptic targeting information. GluN2D-NMDARs are activated by changes in basal glutamate to bidirectionally control GABA release. Importantly, inhibition of GABA release by GluN2C/D modulators and subanesthetic ketamine is absent in mice lacking GluN2D in parvalbumin-interneurons, suggesting that GluN2D-dependent presynaptic regulation of GABA release may underlie some of ketamine's effects. The GluN2C/D-selective inhibitor NAB14 recapitulates durable ketamine-induced enhancement of long-term potentiation (LTP) and recovery of reward motivation in a behavioral model of depression without ketamine's undesirable effects, suggesting that GluN2D-NMDARs could be a therapeutically relevant target.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cites 11
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. The Lancet Psychiatry November 1, 2022
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
- Ketamine: Mechanisms and Relevance to Treatment of Depression. Annual Review of Medicine September 20, 2023
and 6 more in the library