Roles of TRPC3 and TRPC6 in the medial prefrontal cortex in the antidepressant-like actions of ketamine
Satoshi Deyama, Katsuyuki Kaneda
Proceedings for Annual Meeting of The Japanese Pharmacological Society 2021 DOI: 10.1254/jpssuppl.94.0_3-o-e3-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study in mice Peer reviewed |
|---|---|
| Population | Mice with lipopolysaccharide (LPS)-induced depression-like behavior |
| Interventions | Ketamine Pyr3 SAR7334 GSK1702934A BDNF VEGF |
| Measures | tail suspension test, forced swim test, locomotor activity |
| Topics | Esketamine Ketamine |
| Key findings | The authors report that the antidepressant-like actions of ketamine in LPS-treated mice require activation of TRPC3 and TRPC6 in the medial prefrontal cortex. Inhibiting either channel blocked ketamine's effects and those of BDNF or VEGF, while activating the channels produced antidepressant-like effects. They propose TRPC3 and TRPC6 as potential targets for rapid-acting antidepressants. |
Abstract
The antidepressant actions of the NMDA receptor antagonist ketamine require activity-dependent release of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). Our recent study shows a similar requirement for vascular endothelial growth factor (VEGF). Previous studies have reported that both BDNF and VEGF activate TRPC3 and TRPC6 via diacylglycerol production, and that activation of TRPC3 and TRPC6 mediates the neurotrophic effects of BDNF. Here, we examined the roles of TRPC3 and TRPC6 in the mPFC in the antidepressant actions of ketamine in lipopolysaccharide (LPS)-induced depression model mice. In both the tail suspension and forced swim tests, the antidepressant-like actions of ketamine were significantly blocked by intra-mPFC infusion of the selective TRPC3 inhibitor Pyr3 or the selective TRPC6 inhibitor SAR7334. Intra-mPFC infusion of BDNF or VEGF produced antidepressant-like effects, and these antidepressant-like effects were also blocked by intra-mPFC infusion of Pyr3 or SAR7334. Moreover, both systemic and intra-mPFC injection of a TRPC3/TRPC6 activator GSK1702934A produced antidepressant-like effects. These treatments did not significantly affect locomotor activity in LPS-treated mice. The current results indicate that the activation of TRPC3 and TRPC6 as downstream targets of BDNF and VEGF in the mPFC plays an essential role in the antidepressant actions of ketamine. TRPC3 and TRPC6 may be promising targets for the development of novel, rapid-acting antidepressant agents.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |