NMDA receptor function in health and disease: old actors, new dimensions (2023)


Since the discovery of N-methyl-D-aspartate ionotropic glutamate receptors (NMDARs) four decades ago, considerable effort has been devoted to dissecting their multifaceted signaling properties and implications for neurophysiology and pathology. core contribution. Indeed, NMDAR functions include regulation of neuronal migration, synaptogenesis and maturation during development, as well as initiation of long-term synaptic plasticity and fine-tuning of brain network activity and behavior. Impairment of NMDAR signaling thus leads to devastating neurological and psychiatric disorders such as stroke, neurodegenerative disease or schizophrenia, and the underlying mechanisms of NMDAR dysfunction have been under intense scrutiny. NMDARs are tetrameric receptors containing two essential GluN1 subunits, binding glycine or D-serine, encoded by a single gene,grin, with eight splice variants. The GluN1 subunit is associated with two additional subunits: the glutamate-binding GluN2(A-D) subunit or the less common glycine-binding GluN3(A-B) subunit, each encoded by a unique gene.1The various combinations of GluN2 and/or GluN3 subunits that make up NMDARs define the biophysical, pharmacological, and signaling properties of any given NMDAR complex. Structurally, each subunit consists of two extracellular bilobed domains (Figure 1A), the N-terminal domain (NTD) and the agonist-binding domain (ABD)—they are allosteric modulators and Agonist/coagonist site of action - transmembrane domain (TMD) consisting of three helices and a reentrant loop delineating the ionic pore and selectivity filter, and a cytoplasmic C-terminal tail of varying size (50 residues from the shortest isoform of GluN1 to 660 residues, GluN2B) and contain multiple sites of post-translational modifications and protein-protein interactions that allow receptor regulation, anchoring and signal transduction.2NMDAR activation requires the binding of glycine (or D-serine) to the GluN1 subunit and glutamate to the GluN2 subunit, thereby promoting the closure of the ABD "clamshell" and the opening of the ionic pore.3It also requires membrane depolarization-induced removal of voltage-dependent blockage of pores by Mg (Mg2+) and cause a slow decay of the influx of sodium and calcium ions. This influx of ions initiates intracellular signaling pathways that regulate the strength of synaptic connections. Due to the requirement for synchronization of glutamate presynaptic release and postsynaptic depolarization, NMDARs are thought to act as Hebbian coincidence detectors, eliciting synaptic potentiation through well-described mechanisms of long-term potentiation (LTP) and depression (LTD) Or weaken, and thus provide molecular substrates for learning and memory.2Although the ionotropic properties of NMDARs underlie these adaptive processes, a growing body of research suggests that there are other aspects of NMDAR physiology involved in a wide range of brain functions and diseases. The term "non-canonical" is often used to describe those functions of NMDAR that require its presence rather than ion flux. Here, we discuss recent advances in our understanding of the contribution of newly discovered postsynaptic NMDAR signatures to synapse physiology and adaptation, emphasizing activity-dependent redistribution of nanoscale structure and receptor organization as well as nonionic NMDAR Emerging roles of signaling pathways.

partial fragment

NMDAR membrane distribution and organization

From their synthesis in the endoplasmic reticulum to their insertion into synapses, NMDARs follow well-described and recently reviewed pathways through a series of organelles and compartments.4,5,6The number and subunit composition of synaptic and extrasynaptic NMDARs are tightly controlled by a delicate balance between biosynthesis, dendritic transport, exocytosis, lateral diffusion across membrane planes, endocytosis, recycling, and degradation (Figure 1)

Activity-dependent changes in the number of synaptic NMDARs: NMDAR-LTP and -LTD

In addition to their critical role as triggers for the chronic up- or down-regulation of AMPAR numbers that regulate most fast excitatory synaptic transmission, increasing evidence suggests that NMDARs themselves contribute to synaptic message transmission and undergo activity-dependent remodeling and Long-term plasticity, thereby allowing subsequent metaplastic modulation in the amplitude and direction of NMDAR-dependent plasticity of AMPAR-mediated transport.79plasticity

Atypical dysfunction of NMDARs in neurological and psychiatric disorders

Understanding how alterations in NMDAR signaling contribute to the etiology of brain disease has attracted considerable attention over the past few decades.9,137Several putative mechanisms supporting impaired NMDAR signaling have been proposed, ranging from genetic mutations observed in patients with neuropsychiatric disorders to NMDAR antagonists that trigger neuropsychiatric disorders. However, therapeutic attempts to counteract NMDAR dysfunction have been unsuccessful. a possibility

Overview and Future Outlook

Over the years, a body of literature has flourished showing that signaling from ionotropic glutamate receptors cannot be limited to mobile ions, but is also involved in fine-tuning synaptic strength, network activity, and other aspects of behavior.170We highlight here several newly discovered dimensions of NMDAR signaling and highlight how ligand binding and protein-protein interactions alter nanoscale organization and facilitate activity-dependent redistribution

thank you

this work gotNational Center for Scientific Research,European Research Council Synergy Grant(ensemble,#951294);national research institute(ANR-14-OHRI-0001-01,ANR-15-CE16-0004-03,ANR-20-CE16-0023,ANR-22-CE16-0026);Human Frontier Science Program(RGP0019);andNARSAD Young Investigator GrantfromBrain and Behavior Research Foundation(2019 project YIG#27942),medical research foundation, andBordeaux NeuroCampus Seed Program(Tactical). we will

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What is the function of the NMDAR receptor? ›

The N-methyl-D-aspartate (NMDA) receptor is a receptor of glutamate, the primary excitatory neurotransmitter in the human brain. It plays an integral role in synaptic plasticity, which is a neuronal mechanism believed to be the basis of memory formation.

What diseases are associated with NMDA receptors? ›

NMDA receptor (NMDAR) dysfunction has emerged as a common theme in several major nervous system disorders, including ischemic brain injury, chronic neurodegenerative diseases, pain, depression and schizophrenia. Either hyperactivity or hypofunction of NMDARs could contribute to disease pathophysiology.

What are the two conditions that must be met to open NMDA channels? ›

Its ion channel opens only when the following two conditions are met: glutamate is bound to the receptor, and the postsynaptic cell is depolarized (which removes the Mg2+ blocking the channel).

What is unique about the NMDA glutamate receptor? ›

Several unique properties distinguish NMDA receptors from other glutamate receptors, including voltage-dependent block by extracellular Mg2+, high permeability to Ca2+, and the requirement for binding of two coagonists, glutamate and glycine (or d-serine), for channel activation (Traynelis et al., 2010).

What happens when NMDA receptors are activated? ›

NMDA receptors are now understood to critically regulate a physiologic substrate for memory function in the brain. In brief, the activation of postsynaptic NMDA receptors in most hippocampal pathways controls the induction of an activity-dependent synaptic modification called long-term potentiation (FTP).

What is the role of NMDA in depression? ›

A class of drugs called NMDA (N-methyl-D-aspartate) receptor antagonists may be the answer for people with depression who don't get relief from typical treatment. These drugs are safe and effective and tend to work more quickly than most antidepressants when taken under careful medical supervision.

What are the benefits of NMDA? ›

NMDA (short for N-methyl-D-aspartate) receptor antagonists are a class of drugs that may help treat Alzheimer's disease, which causes memory loss, brain damage, and, eventually, death.

Is NMDA autoimmune? ›

Anti-NMDA receptor encephalitis is a neurologic disease first identified by Dr. Josep Dalmau and colleagues at the University of Pennsylvania in 2007. It is an autoimmune disease, where the body creates antibodies against the NMDA receptors in the brain.

What drugs of abuse on the NMDA receptor? ›

Some NMDA receptor antagonists, such as ketamine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N2O), are sometimes used as recreational drugs, for their dissociative, hallucinogenic, and euphoriant properties.

What activates NMDA receptors? ›

Coagonists Glutamate and Glycine. NMDARs are unique among ligand-gated ion channels in that their activation requires binding of two coagonists, glycine and L-glutamate [64–66].

What is the difference between NMDA and GABA? ›

Specifically, GABAB receptors affect the expression, activity and signaling of glutamate receptors under physiological and pathological conditions. Conversely, NMDA receptor activity differentially regulates GABAB receptor subunit expression, signaling and function.

Which cognition requires NMDA a receptor? ›

NMDA receptors (NMDARs) play an important role in neural plasticity including long-term potentiation and long-term depression, which are likely to explain their importance for learning and memory.

What does the NMDA receptor do to dopamine? ›

N-methyl-D-aspartate (NMDA) and dopamine (DA) receptors and their interactions control an incredible variety of functions in the intact brain and, when abnormal, these interactions underlie and contribute to numerous disease states.

How does NMDA receptor affect dopamine? ›

Ventral Midbrain NMDA Receptor Blockade: From Enhanced Reward and Dopamine Inactivation. Glutamate stimulates ventral midbrain (VM) N-Methyl-D-Aspartate receptors (NMDAR) to initiate dopamine (DA) burst firing activity, a mode of discharge associated with enhanced DA release and reward.

What is the only NMDA receptor antagonist on the market? ›

Memantine is an antagonist of the NMDA (N-Methyl-D-Aspartate)-receptor subtype of glutamate receptor. It is used to slow the neurotoxicity thought to be involved in Alzheimer disease and other neurodegenerative diseases.

How does NMDA affect memory? ›

Blocking the NMDAR in the mouse brain impairs synaptic plasticity and compromises learning and memory. Conversely, genetic enhancement of NMDAR function improves memory in adult mice.

How does NMDA affect GABA? ›

NMDA receptor activation enhances inhibitory GABAergic transmission onto hippocampal pyramidal neurons via presynaptic and postsynaptic mechanisms.

How do you stimulate NMDA receptors? ›

The activation of NMDA receptor requires binding of a ligand (glutamate) to the GluN2 subunits, membrane depolarization to remove the Mg2+ block of the channel, and binding of an essential co-agonist, glycine to the GluN1 subunits.

Is magnesium an NMDA antagonist? ›

Zinc and magnesium, the potent antagonists of the NMDA receptor complex, are involved in the pathophysiology of depression and exhibit antidepressant activity.

What are NMDA receptors for dummies? ›

What are the NMDA receptors? NMDA receptor is a type of G protein-coupled ionotropic glutamate receptor that plays a crucial role in regulating a wide variety of neurological functions, including breathing, locomotion, learning, memory formation, and neuroplasticity.

What are the symptoms of NMDA dysfunction? ›

Although the definitive role of NMDA neurotransmission in BPSD still needs to be elucidated, NMDAR dysfunction is indeed involved in psychiatric and behavioral symptoms, such as agitation, depression, anxiety and psychotic symptoms. In animal models, NMDAR dysfunction is associated with agitation and aggression.

Is NMDA hereditary? ›

In most cases, anti-NMDAR encephalitis does not seem to be an inherited condition. Some studies have found an association between the disease and specific genetic mutations, but these changes usually occur during sperm or egg development and are not carried by a child's parents.

What antibodies are against NMDA receptor? ›

Anti NMDAR encephalitis is a relatively common autoimmune encephalitis characterized by complex neuropsychiatric features and the presence of Immunoglobulin G (IgG) antibodies against the NR1 subunit of the NMDA receptors in the central nervous system (CNS).

Does alcohol block NMDA receptors? ›

Our lab and others showed that alcohol inhibits the gating of the NMDA receptor- ion channel, so that it spends less time in the open state, and as a result is less able to stimulate the cell.

Does serotonin block NMDA? ›

We found that serotonin, by activating 5-HT1A receptors, inhibits NMDAR currents through a mechanism dependent on the motor protein-mediated transport of NMDA receptors along microtubules in dendrites.

Which antidepressant is an NMDA antagonist? ›

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression.

Where are NMDA receptors found in the body? ›

NMDA receptors are found in the peripheral nervous system as well as the central terminal of primary afferent neurons and have been shown to play an important role in regulating the release of nociceptive neurotransmitters.

Is magnesium a NMDA agonist? ›

Magnesium is a NMDA receptor antagonist. Magnesium plays an important role in neuronal cellular physiology by competing with Ca2+ ions, acting as an endogenous Ca2+ channel blocker and gating NMDA receptor-associated ion channels [89].

Is magnesium an NMDA? ›

On a molecular level, magnesium ion was identified as an NMDA receptor open channel blocker and neuronal depolarization can relieve the Mg2+ block (Mayer et al., 1984; Nowak et al., 1984; Mayer and Westbrook, 1987); hence, Mg2+ is considered a voltage dependent NMDAR open channel blocker.

Does gabapentin inhibit NMDA? ›

Gabapentin reduces neuropathic pain primarily by targeting a2d-1-bound NMDA receptors.

Do NMDA receptors release GABA? ›

Opening of the NMDA receptors provides a direct Ca2+ route for triggering GABA release to complete the feedback circuit, while the major role of non-NMDA receptors appears to be facilitating the action of NMDA receptors by relieving Mg2+ blockade.

Is bupropion an NMDA antagonist? ›

Dextromethorphan/bupropion is an orally administered, rapidly-acting, investigational NMDA receptor antagonist with multimodal activity.

Is NMDA a GABA receptor? ›

GABAA (gamma-aminobutyric acid type A) receptors and NMDA (N-methyl-D-aspartate) receptors are both examples of ligand-gated, heteromeric neurotransmitter receptors whose cell-surface expression is dynamic and tightly regulated. NMDA receptors are localized at excitatory synapses.

Which Alzheimer's drug is an NMDA antagonist? ›

Memantine is an antagonist of the NMDA (N-Methyl-D-Aspartate)-receptor subtype of glutamate receptor. It is used to slow the neurotoxicity thought to be involved in Alzheimer disease and other neurodegenerative diseases.

What is the mechanism of action of NMDAR? ›

The mechanism by which NMDA-dependent LTD reduces synaptic strength is to reverse the effects of LTP: dephosphorylation of AMPARs, thus reducing their open probability [23] and removal of AMPARs from the synaptic plasma membrane by endocytosis (see Chapter 8).

What do NMDA receptors respond to? ›

The NMDA receptor (NMDAR) is an ion-channel receptor found at most excitatory synapses, where it responds to the neurotransmitter glutamate, and therefore belongs to the family of glutamate receptors.

What is the primary role of NMDA receptors in learning? ›

The N-methyl-D-aspartate (NMDA) receptor (NMDAR) is the predominant molecular device for controlling synaptic plasticity and memory function.

How does NMDAR activation regulates the daily rhythms of sleep and mood? ›

NMDAR activation improves sleep and mood by facilitating these behaviors at the appropriate times of day. The ability of the lights-off stimulus to trigger a rapid and long-lasting increase in activity and positive affect appears to be a naturalistic form of NMDAR-dependent behavioral plasticity.

What is the mechanism of action primarily involving NMDA receptor antagonism? ›

When the glutamate level increases in the brain, it causes excess release of calcium, which can damage the nerve cells. NMDA antagonists bind to NMDA receptors and prevent the binding of glutamate, thereby preventing the release of calcium into the nerve cells.

What does an NMDA receptor antagonist do and what is an example of one? ›

NMDA (short for N-methyl-D-aspartate) receptor antagonists are a class of drugs that may help treat Alzheimer's disease, which causes memory loss, brain damage, and, eventually, death. There's no cure for Alzheimer's, but some drugs may slow it down.

What are the effects of NMDA receptor antagonism? ›

Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares, catatonia, ataxia, anesthesia, and learning and memory deficits.

What is the role of NMDA receptors in learning and memory? ›

NMDA receptors along with other iGluRs, such as α-amino-3-hydroxy-5-methylisoxazole-4-isoxazopropionic acid (AMPA) and Kainate, are critical for the rapid regulation of synaptic plasticity including long-term potentiation and long-term depression, which are important cellular correlates for learning and memory function ...


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