ON or OFF?: Modulating the N-Methyl-D-Aspartate Receptor in Major Depression.

Shi Yu Chan,Philip W J Burnet,Edward Matthews

doi:10.3389/fnmol.2016.00169

Abstract

Since the discovery that a single dose of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, had rapid and long-lasting antidepressant effects, there has been increased interest in using NMDAR modulators in the pharmacotherapy of depression. Ketamine’s efficacy seems to imply that depression is a disorder of NMDAR hyperfunctionality. However, studies showing that not all NMDAR antagonists are able to act as antidepressants challenge this notion. Furthermore, NMDAR co-agonists have also been gaining attention as possible treatments. Co-agonists such as D-serine and sarcosine have shown efficacy in both pre-clinical models and human trials. This raises the question of how both NMDAR antagonists and agonists are able to have converging behavioral effects. Here we critically review the evidence and proposed therapeutic mechanisms for both NMDAR antagonists and agonists, and collate several theories on how both activation and inhibition of NMDARs appear to have antidepressant effects.

Highlights

The N-methyl-D-aspartate receptors (NMDARs) are a class of ionotropic glutamate receptors that are widely expressed in the brain
Given that NMDARs are composed of different subunits, some emphasis has been placed on the differential physiological properties of receptors composed of different subunit subtypes, FIGURE 2 | Illustration of a complementary mechanism providing an explanation for how both NMDAR co-agonists and antagonists are able to lead to similar downstream antidepressant effects. (A) Differential activation of NMDARs based on location: tonic activation of extra-synaptic NMDARs by ambient/spontaneous glutamate release lead to inactivation of the mammalian target of rapamycin signaling complex and the inhibition of protein synthesis
The modulation of the NMDAR as a potential therapeutic strategy for major depression is supported by compelling evidence, though existing clinical data have not yet eluded to a pathophysiological role of NMDARs in this disorder

Summary

INTRODUCTION

The N-methyl-D-aspartate receptors (NMDARs) are a class of ionotropic glutamate receptors that are widely expressed in the brain. Memantine neither induced eEF2 de-phosphorylation nor increased BDNF expression (Gideons et al, 2014), and its activity is not affected by mTOR inhibition (Sabino et al, 2013) Another theory for these differential effects of memantine and ketamine is that they could be binding to distinct NMDAR ‘‘subpopulations’’ (Johnson et al, 2015), which might include NMDAR subunit composition and/or synaptic location, though this remains controversial (Wroge et al, 2012; Emnett et al, 2013; Gideons et al, 2014). The antidepressant effects of sarcosine can, be attributed to the inhibition of synaptic glycine uptake, and/or direct NMDAR stimulation Overall it appears that mTOR signaling and AMPARs are common downstream targets of both NMDAR agonists and antagonists. The reverse is true for depression where doses above 250 mg are necessary to observe antidepressant effects in an add-on clinical trial (Heresco-Levy et al, 2013), suggesting that DCS’s antidepressant effects are achieved when it acts as an NMDAR antagonist

AMPAR CONVERGENCE

NMDAR SUBTYPE SPECIFICITY AND LOCALIZATION

CONCLUSION

AUTHOR CONTRIBUTIONS