Introduction

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. NMDA receptors also appear to have involvement in a process called excitotoxicity. Excitotoxicity may play a role in the pathophysiology of a variety of diseases such as epilepsy or Alzheimer disease. Many drugs inhibit NMDA receptors, including ketamine and phencyclidine, two common drugs of abuse.

Cellular Level

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. It binds to several different receptors, such as the AMPA, NMDA, and kainate receptors, each named after the laboratory molecule that selectively binds to them. These receptors often work in concert with one another in complex networks. The NMDA receptor is ionotropic and controls a ligand-gated ion channel. It is particularly important because it is integral in the processes of long-term potentiation, synaptic plasticity, and memory formation.[1]

There are multiple subtypes of NMDA receptors. Each receptor consists of two N1 subunits with either two N2 or two N3 subunits. The N1/N2 NMDA receptor complex is of primary physiological relevance. The receptor has several parts, including an extracellular ligand-binding domain and a transmembrane ion channel. When a ligand binds to the NMDA receptor, the ligand-binding domain closes like a clamshell. This closure leads to an opening of the transmembrane ion channel. The transmembrane ion channel is nonspecific for positively charged ions. However, due to the chemical properties of the channel and the concentrations of ions outside the cell, calcium ion often passes through the channel.[2] 

Regulation of the transmembrane ion channel is complex and multifactorial, allowing for precise control of ion permeability in physiologic conditions. Disruption of this regulation can be lethal to the cell. For the ion channel to open, several things must happen simultaneously. First, two molecules of either glycine or serine must bind to the NMDA receptor. Glycine will bind to extrasynaptic receptors; serine will bind to receptors located within the synapse. Second, two molecules of glutamate must bind to the receptor. However, the channel may not open even if it meets both of these. Magnesium and zinc both bind to sites on the NMDA receptor and block the transmembrane ion channel. This blockage prevents calcium ions from entering. For the channel to be permeable to calcium, magnesium or zinc must be dislodged from the cell by depolarization of the postsynaptic neuron. If another glutamate receptor, such as an AMPA receptor, is activated, it can depolarize the postsynaptic cell and dislodge magnesium or zinc, allowing the channel to open. In this way, the NMDA receptor serves as a coincidence detector. The channel will only open if the postsynaptic cell depolarizes at the same time that glutamate enters the synapse. Additionally, this allows a graded response to stimuli.[3] 

Three possible responses can occur, including short-term potentiation, long-term potentiation, and excitotoxicity. 

A small depolarization of the postsynaptic cells only partially dislodges magnesium or zinc, allowing a small number of calcium ions to enter the cell. These calcium ions serve as second messengers, which temporarily recruit more AMPA receptors to the cell. This recruitment allows for a higher chance of future depolarization. The effect of this change will only last for a few hours at most, so this process is known as short-term potentiation.

A large depolarization will completely dislodge magnesium or zinc, allowing a large volume of calcium to enter the cell. This calcium can interact with transcription factors, encouraging the growth of the neuron. This growth is known as long-term potentiation and is the mechanism behind synaptic plasticity. Synaptic plasticity is the brain's ability to "re-wire" itself. These effects can last for years.

An overwhelmingly prolonged depolarization will allow unregulated passage of calcium into the cell, which is lethal to it, and this effect is known as excitotoxicity. This process is known to occur in a multitude of neurological diseases.

Development

NMDA receptors are integral to the development of the brain. They help in the maturation of various glutamatergic synapses. Knockout studies of different NMDA receptor subunits have demonstrated neurologic deficits in animal models, such as failure to develop orientation selectivity in the visual cortex. NMDA receptors are involved in the regulation of synaptic plasticity and thus impact the lifelong development of the brain. Much research remains to elucidate the precise mechanisms of the NMDA receptor on brain development.[4]

Organ Systems Involved

The NMDA receptor has an integral role in synaptic plasticity and can delicately control ion permeability into the cell. Therefore, it is not surprising that it is virtually ubiquitous throughout the central nervous system. For example, roughly 80% of cortical neurons feature NMDA receptors. They preferentially express on pyramidal neurons. Curiously, they are also present on astrocytes, glial cells traditionally thought to support neurons.[5] NMDA receptors are also present within the hippocampus, where they appear to play a crucial role in memory formation.

NMDA receptors exist within the peripheral nervous system.[6] NMDA receptor subunits are also expressed in the kidney and cardiovascular system of the rat, though their purposes are unclear.[7]

Function

NMDA receptors are involved in myriad functions within the central nervous system.[6] Because this receptor allows a graded response to stimuli and precise control over calcium entry into the cell, it impacts many central nervous system functions. A classic example of NMDA receptor functionality is the acquisition of new memories. This memory encoding occurs via the process of long-term potentiation. The current belief is that the hippocampus is a critical brain area for this process.[8]

Pathophysiology

The NMDA receptor is involved in a variety of disease states, including: 

• Alzheimer disease: NMDA receptors become severely disordered in this disease, a progressive and debilitating neurodegenerative disorder of unclear etiology. While the precise mechanisms of this remain unclear, it is well known that memantine, an NMDA receptor uncompetitive antagonist, improves Alzheimer symptoms.[9]
• Huntington disease: This is a hereditary neurodegenerative disorder that also involves NMDA receptor-mediated excitotoxicity.[10] Memantine and amantadine, both NMDA receptor antagonists, reduce symptoms of Huntington disease.[11][12]
• Epilepsy, stroke, and traumatic brain injury: These events involve calcium-mediated excitotoxicity. For example, in epilepsy, uncontrolled neuronal firing leads to excitotoxicity and permanent brain damage. It appears that similar processes occur in stroke and traumatic brain injury.[13]
• Major depressive disorder: NMDA receptors may be involved in major depressive disorder, as ketamine, an NMDA receptor antagonist, has shown promise in its treatment.[14]
• Tinnitus: NMDA receptors may be involved in the pathophysiology of tinnitus.[15]
• Anti-NMDA receptor encephalitis: This is a rare, potentially lethal autoimmune encephalitis where autoantibodies are produced against the NMDA receptor. Patients present with psychiatric changes, epilepsy, motor, speech, or autonomic dysfunction, as well as decreased levels of consciousness. The diagnosis is by collecting anti-NMDA receptor antibodies from the patient's cerebrospinal fluid. This disease provides an excellent example of the ubiquity of NMDA receptors. When attacked by an autoimmune disease, dysfunction in numerous neurologic functions occurs. Treatment commonly involves steroids, intravenous immunoglobulin, and plasma exchange therapy. Anti-NMDA receptor encephalitis is often associated with ovarian teratomas.[16]
• Heavy metal poisoning: Evidence suggests that in heavy metal poisoning, metals such as lead bind to NMDA receptors and may exert some of their toxic effects there.[17]
• Migraines: Magnesium is a treatment for migraines, and NMDA receptors may be involved in their pathogenesis.[18][19]

Clinical Significance

Aside from their involvement in many disease pathophysiologies, NMDA receptors are the pharmacologic target of both therapeutic drugs and drugs of abuse. Several examples of these include: 

• Ketamine: An NMDA antagonist, it is used as a sedative, anesthetic, off-label as an antidepressant, or recreationally as a hallucinogenic drug of abuse.[20]
• Phencyclidine: An NMDA antagonist. It is used recreationally as a hallucinogenic, depersonalizing, euphoric drug of abuse. It reportedly causes homicidal and suicidal impulses in users. Users will characteristically experience nystagmus on physical exam.[21]
• Ethanol: A common recreational drug, it modulates NMDA receptors through complex mechanisms.[22]
• Memantine: An uncompetitive NMDA antagonist, this drug is used in the treatment of Alzheimer disease and off-label for Huntington disease.
• Amantadine: An NMDA antagonist used in the treatment of Parkinson disease and off-label for Huntington disease.[23]
• Magnesium: This naturally occurs in the transmembrane ion channel of the NMDA receptor. It is used to prevent migraines and abort migraine aura, prevent seizures in preeclampsia, and as a neuroprotective agent administered to mothers of premature infants to prevent neonatal brain damage.[24]
• Methadone: A mu-opioid agonist and NMDA antagonist used in the treatment of opioid addiction.[25]