Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments

Abstract

The underlying neurobiological basis of major depressive disorder remains elusive due to the severity, complexity, and heterogeneity of the disorder. While the traditional monoaminergic hypothesis has largely fallen short in its ability to provide a complete picture of major depressive disorder, emerging preclinical and clinical findings suggest that dysfunctional glutamatergic neurotransmission may underlie the pathophysiology of both major depressive disorder and bipolar depression. In particular, recent studies showing that a single intravenous infusion of the glutamatergic modulator ketamine elicits fast-acting, robust, and relatively sustained antidepressant, antisuicidal, and antianhedonic effects in individuals with treatment-resistant depression have prompted tremendous interest in understanding the mechanisms responsible for ketamine's clinical efficacy. These results, coupled with new evidence of the mechanistic processes underlying ketamine's effects, have led to inventive ways of investigating, repurposing, and expanding research into novel glutamate-based therapeutic targets with superior antidepressant effects but devoid of dissociative side effects. Ketamine's targets include noncompetitive N-methyl-D-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid throughput potentiation coupled with downstream signaling changes, and N-methyl-D-aspartate receptor targets localized on gamma-aminobutyric acid-ergic interneurons. Here, we review ketamine and other potentially novel glutamate-based treatments for treatment-resistant depression, including N-methyl-D-aspartate receptor antagonists, glycine binding site ligands, metabotropic glutamate receptor modulators, and other glutamatergic modulators. Both the putative mechanisms of action of these agents and clinically relevant studies are described.

Figure 1.

Proposed mechanisms of action of glutamatergic modulators and other putative rapid-acting antidepressants. Disinhibition hypothesis: Ketamine and esketamine selectively block N-methyl-D-aspartate receptors (NMDARs). These are expressed on gamma-aminobutyric acid (GABA)-ergic inhibitory interneurons, and their blockade decreases interneuron activity that, in turn, leads to disinhibition of pyramidal neurons and enhanced glutamatergic firing. Glutamate then binds to and activates post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Inhibition of spontaneous NMDAR-mediated transmission: Alternatively, ketamine may induce rapid brain-derived neurotrophic factor (BDNF) translation in the hippocampus, reduce phosphorylation, and activate eukaryotic elongation factor 2 (eEF2). Ketamine may also preferentially bind to NMDARs and affect neuronal NMDAR-mediating spontaneous excitatory transmission, which at rest keeps eEF2 phosphorylated and inhibits BDNF synaptic translation. De-suppression of BDNF translation then contributes to changes in synaptic plasticity that mediate ketamine’s antidepressant effects. AMPAR activation is also necessary for these effects. Inhibition of extra-synaptic NMDARs: Ketamine selectively blocks extra-synaptic GluN2B-containing NMDARs, which are tonically activated by low levels of ambient glutamate regulated by the excitatory amino acid transporter 2 (EAAT2) located on astrocytes. Inhibition of the extra-synaptic GluN2B-NMDARs de-suppresses mammalian target of rapamycin complex 1 (mTORC1) function, which in turn induces protein synthesis. Blockade of spontaneous NMDAR activation inhibits eEF2 kinase (eEF2K) activity, thus preventing phosphorylation of its eEF2 substrate. This effect subsequently enhances BDNF translation and, ultimately, protein synthesis. Inhibition of lateral habenula (LHb) neurons: In animal models, local neuronal firing in a single brain region known as the lateral habenula (LHb) drives significant depressive-like behaviors. Ketamine decreases burst activity in the LHb by blocking NMDAR-dependent burst activity in the LHb and disinhibiting the downstream activity of midbrain dopaminergic neurons and serotoninergic neurons, which are responsible for activating the reward centers in the brain. Local blockade of NMDARs or low-voltage-sensitive T-type voltage sensitive calcium channels (T-VSCCs) in the LHb sufficed to induce rapid antidepressant effects. The role of ketamine metabolites: (2R,6R)-hydroxynorketamine (HNK) exerts NMDAR inhibition-independent antidepressant actions by activating AMPAR-mediated synaptic potentiation. Other glutamatergic modulators: Metabotropic glutamate receptor (mGluR) 2/3 antagonists are thought to enhance synaptic glutamate levels, thereby boosting AMPAR transmission and firing rates and extracellular monoamine levels. GLYX-13, which has partial agonist properties at NMDARs, is hypothesized to activate mTORC and subsequently induce protein synthesis. GLYX-13 requires AMPA and activity-dependent BDNF release, but unlike ketamine does not produce glutamate bursts. AMPAR activation enhances BDNF release, activates the tropomyosin receptor kinase B (TrkB) receptor, and subsequently promotes protein synthesis by activating the mTORC complex. AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; GAD, glutamate decarboxylase; Gαs, G alpha subunits; Gln, glutamine; GLT-1, glutamate transporter 1; Glu, glutamate; GSK-3, glycogen synthase kinase 3; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor. Adapted with permission from (Lener et al., 2017; Zanos et al., 2018a).