N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity

Abstract

Uncompetitive NMDAR (N-methyl-D-aspartate receptor) antagonists restore impaired neural plasticity, reverse depressive-like behavior in animal models, and relieve major depressive disorder (MDD) in humans. This review integrates recent findings from in silico, in vitro, in vivo, and human studies of uncompetitive NMDAR antagonists into the extensive body of knowledge on NMDARs and neural plasticity. Uncompetitive NMDAR antagonists are activity-dependent channel blockers that preferentially target hyperactive GluN2D subtypes because these subtypes are most sensitive to activation by low concentrations of extracellular glutamate and are more likely activated by certain pathological agonists and allosteric modulators. Hyperactivity of GluN2D subtypes in specific neural circuits may underlie the pathophysiology of MDD. We hypothesize that neural plasticity is epigenetically regulated by precise Ca²⁺ quanta entering cells via NMDARs. Stimuli reach receptor cells (specialized cells that detect specific types of stimuli and convert them into electrical signals) and change their membrane potential, regulating glutamate release in the synaptic cleft. Free glutamate binds ionotropic glutamatergic receptors regulating NMDAR-mediated Ca²⁺ influx. Quanta of Ca²⁺ via NMDARs activate enzymatic pathways, epigenetically regulating synaptic protein homeostasis and synaptic receptor expression; thereby, Ca²⁺ quanta via NMDARs control the balance between long-term potentiation and long-term depression. This NMDAR Ca²⁺ quantal hypothesis for the epigenetic code of neural plasticity integrates recent psychopharmacology findings into established physiological and pathological mechanisms of brain function.

Keywords: AMPA; Ca2+; Mg2+; NMDA; endorphins; glutamate; major depressive disorder; neural plasticity.

Figure 1

The depressive phenotype, impaired neural plasticity, and uncompetitive NMDAR antagonists: psychopharmacology of dysfunctional synapses in depression. (A) Receptor cell → first-order neuron synapse in patients with depression. At resting membrane potential, hyperactive postsynaptic NMDARs determine excessive Ca²⁺ influx, leading to chronic hyper-activation of CaMKIII-eEF2 signaling and downstream effectors, causing unavailability of synaptic proteins in neurons within brain circuits relevant to depression. (B) Low potency uncompetitive NMDAR antagonists preferentially block GluN2D channels in the open conformation and free of Mg²⁺ during resting membrane potential. The decreased influx of GluN2D-mediated Ca²⁺ restores synaptic protein homeostasis through down modulation of the CaMKIII-eEF2 pathway and re-activation of downstream effectors. Postsynaptic protein homeostasis enables physiological neural plasticity and determines the resolution of the depressive phenotype. Solid lines represent activated pathways/biological processes; dashed lines indicate attenuated pathways/biological processes.

Figure 2

Physiological stimulus-driven NMDAR-mediated Ca²⁺ regulated neural plasticity at resting and at phasic membrane potential. The figure depicts a receptor cell → first-order neuron synapse following depolarizing or hyper-polarizing stimuli. At resting membrane potential, subthreshold stimuli are reaching the receptor cell (center figure) with tonic release of glutamate, activating a small fraction of AMPARs and NMDARs, resulting in preferential GluN2D graded postsynaptic influx of Ca²⁺ quanta. Tonic NMDAR-mediated graded Ca²⁺ influx (preferentially via GluN2D subtypes) directs synaptic protein homeostasis. When depolarizing stimuli reach the receptor cell (left figure), there is a massive release of glutamate into the synaptic cleft. This release activates all postsynaptic ionotropic receptors, e.g., ”fast” Na⁺ permeable AMPARs“and ”slow” Ca²⁺ permeable NMDARs. For completeness, we also show the response to stimuli resulting in receptor cell hyperpolarization (right figure), e.g., visual stimuli reaching photoreceptors, with a reduction in the tonic release of glutamate. Reduced glutamate release leads to a graded reduction in NMDAR-mediated Ca²⁺ entry into the postsynaptic neuron.

Figure 3

Stimulus-induced NMDAR-regulated Ca²⁺ quanta and “hot spot” neural plasticity (1–6) receptor cell → first-order synaptic neuron. (1) Resting membrane potential: Stimuli reach the receptor cell and change its membrane potential, regulating the activity of presynaptic NMDARs. Based on the frequency and intensity of incoming stimuli, graded Ca²⁺ quanta via presynaptic NMDARs instruct the receptor cell on glutamate vesicle density. When presynaptic glutamate vesicles reach the density threshold, one or more vesicles fuse with the membrane of the receptor cell and release glutamate. Free glutamate released at graded resting membrane potential activates a small percentage of glutamate receptors, including AMPARs and NMDARs, at the “hot spot” of the first order neuron. The low nanomolar concentration of free glutamate preferentially activates GluN2D subtypes. (2) Action potential: When depolarizing stimuli reach the receptor cell, release of glutamate occurs from all vesicles juxtaposed to the membrane, leading to massive activation of “hot spot” postsynaptic glutamate receptors, including AMPARs and NMDARs. (3) Coincidental AMPAR-mediated depolarization (“fast” Na⁺ influx) causes Mg²⁺ release from open-conformation NMDARs bound by glutamate, initiating NMDAR-regulated “slow” Ca²⁺ influx. Excitatory Amino Acid Transporters (EAATs) re-uptake free glutamate from the synaptic cleft, terminating the action potential. (4) NMDAR-regulated postsynaptic Ca²⁺ quanta activate enzymatic pathways, leading to the transcription of genes encoding synaptic proteins. Synthesized proteins are then transported (trafficking) to the synapse and undergo local assembly and expression at the synaptic membrane (receptor subunits and scaffolding proteins) or are released in the synaptic cleft (neurotrophic factors). (5) After depolarizing stimuli, EAAT activity restores resting membrane potential. Subthreshold stimuli at resting membrane potential again induce graded glutamate release, and graded activation of AMPARs and NMDARs, leading to preferential GluN2D-regulated postsynaptic Ca²⁺ influx, instructing synaptic protein homeostasis. Stimuli induce neural plasticity at the synaptic “hot spot”: the synaptic framework (type and density of receptors) and availability of synaptic proteins (receptor subunits, neurotrophic factors, and scaffolding proteins) are regulated by incoming stimuli or lack of thereof (points 2–4). (6) Subsequent tonic or depolarizing stimuli trigger graded or massive glutamate release into the synaptic cleft, activating AMPARs and NMDARs, directing graded or massive NMDARs influx of Ca²⁺ quanta, respectively, and downstream enzymatic activation. Free glutamate is then re-up-taken via EAATs. The epigenetic code, how keys change locks: after each stimulus, Ca²⁺ quanta and intracellular enzymatic pathways activation will be different compared to before the stimulus, due to stimulus-induced changes in the “hot spot” receptor framework. The constant stimulus-dependent changes in the receptor framework will determine NMDAR-regulated Ca²⁺ quanta influx, constantly accounting for prior stimuli. The synaptic framework at the “hot spot” precisely gates glutamate-induced NMDAR Ca²⁺ quanta influx and downstream events constantly shaping LTP/LTD in neural circuits relevant to incoming stimuli.