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

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.

Keywords: NMDAR antagonist; depression; glycine site; mTOR; subunit.

Figure 1

Summary of the mechanisms of how N-methyl-D-aspartate receptor (NMDAR) antagonists (direct inhibition and disinhibition) and co-agonists lead to antidepressant effects. The indirect hypothesis proposes that NMDAR antagonists inhibit the basal activation of inhibitory interneurons, resulting in disinhibition of pyramidal neurons. The direct hypothesis proposes that NMDAR antagonists inhibit basal activation of pyramidal neurons (caused by spontaneous or ambient glutamate) that in turn inhibits protein synthesis. The co-agonist hypothesis proposes that NMDAR co-agonists activate signaling pathways in pyramidal neurons that result in increased synaptic plasticity. Both NMDAR antagonists and agonists activate signaling pathways that result in increased protein translation and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, leading to increased LTP induction, synaptic plasticity and antidepressant behavior.

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 (mTOR) signaling complex and the inhibition of protein synthesis. On the other hand, action-potential stimulated release of glutamate and the presence of the synaptic co-agonist D-serine leads to activation of synaptic NMDARs, triggering pathways that lead to protein synthesis and synaptic plasticity. (B) Main proposed mechanism underlying complementary antidepressant effects of NMDAR antagonists and agonists: NMDAR antagonists, such as ketamine, inhibit the tonic activation of extra-synaptic NMDARs, resulting in activation of the mTOR signaling complex and protein synthesis. Administration of NMDAR co-agonists, such as D-serine, occupy un-saturated glycine sites on NMDARs, stimulating synaptic NMDARs and leading to LTP and antidepressant effects. Ketamine binding at synaptic sites is not represented.