Physiology, NMDA Receptor


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Benjamin Jewett


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Updated:
10/27/2018 12:31:45 PM

Introduction

The N-methyl-D-aspartate (NMDA) receptor is a ligand 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 are also thought to be involved 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

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 both of these conditions are met. 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 post-synaptic 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 occurs 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 be done 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 are preferentially expressed 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 are believed 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. It is believed 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 are 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’s 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 is believed 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. It is diagnosed 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: It is believed 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 has been reported to cause 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, it 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]

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Physiology, NMDA Receptor - Questions

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Study of functional properties of various receptors made from coronal brain slices uses whole cell voltage clamp recordings. A holding potential of -70 mV is established. Bath application of receptor agonists for 4 different types consistently elicited either inhibitory or excitatory postsynaptic currents. One receptor only elicited a postsynaptic response at a holding potential of 0 mV. This receptor is most likely which of the following?



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Which ion blocks the resting membrane potential of N-methyl aspartic acid receptors?



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Which of the following is not true about the NMDA receptor?



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A 24-year-old man is brought to the emergency department by law enforcement after he violently attacked a customer in a store. In the emergency department, he exhibits extreme aggression, and vertical nystagmus is noted on physical exam. Later, urinary toxicology screen is positive for phencyclidine, a drug that antagonizes NMDA receptors. Which of the following is true about NMDA receptors?



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A 30-year-old man with a past medical history of uncontrolled epilepsy is brought to the emergency department by emergency medical services after experiencing a seizure lasting over 45 minutes. He is given appropriate treatment in the emergency department and admitted to the hospital. However, later in his stay, it is revealed that he is suffering from brain damage from his seizure. The man's brother, a cell biologist, asks how the seizure damaged his brain. Which of the following in an appropriate response?



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A 28-year-old G1P0 at 28 weeks presents to the labor and delivery department after experiencing a rush of fluid and regular contractions. The cervical exam is consistent with preterm labor. The obstetrics resident immediately administers corticosteroids and magnesium. She informs her medical student that magnesium has been shown to protect the brain of the premature infant. Which of the following is true about magnesium in the central nervous system?



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A student is working with a psychiatrist evaluating patients at a busy emergency department. The psychiatrist asks the student which recreational drugs exert their direct effect on the NMDA receptor. Which of the following would be a correct answer?



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Physiology, NMDA Receptor - References

References

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Vyklicky V,Korinek M,Smejkalova T,Balik A,Krausova B,Kaniakova M,Lichnerova K,Cerny J,Krusek J,Dittert I,Horak M,Vyklicky L, Structure, function, and pharmacology of NMDA receptor channels. Physiological research. 2014     [PubMed]
Kandel ER,Dudai Y,Mayford MR, The molecular and systems biology of memory. Cell. 2014 Mar 27     [PubMed]
Ewald RC,Cline HT, NMDA Receptors and Brain Development null. 2009     [PubMed]
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Molero P,Ramos-Quiroga JA,Martin-Santos R,Calvo-Sánchez E,Gutiérrez-Rojas L,Meana JJ, Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review. CNS drugs. 2018 May 7     [PubMed]
Noreña AJ, Revisiting the cochlear and central mechanisms of tinnitus and therapeutic approaches. Audiology     [PubMed]
Liu CY,Zhu J,Zheng XY,Ma C,Wang X, Anti-N-Methyl-D-aspartate Receptor Encephalitis: A Severe, Potentially Reversible Autoimmune Encephalitis. Mediators of inflammation. 2017     [PubMed]
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Lauritzen M, Pathophysiology of the migraine aura. The spreading depression theory. Brain : a journal of neurology. 1994 Feb     [PubMed]
Bigal ME,Bordini CA,Tepper SJ,Speciali JG, Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia : an international journal of headache. 2002 Jun     [PubMed]
Abdallah CG,Sanacora G,Duman RS,Krystal JH, The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacology     [PubMed]
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Raupp-Barcaro IF,Vital MA,Galduróz JC,Andreatini R, Potential antidepressant effect of amantadine: a review of preclinical studies and clinical trials. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999). 2018 Jun 11     [PubMed]
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Aiyer R,Mehta N,Gungor S,Gulati A, A Systematic Review of NMDA Receptor Antagonists for Treatment of Neuropathic Pain in Clinical Practice. The Clinical journal of pain. 2018 May     [PubMed]

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