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.
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.
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.
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.
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.
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.
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. NMDA receptors are also present within the hippocampus, where they are believed to play a crucial role in memory formation.
NMDA receptors are involved in myriad functions within the central nervous system. 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.
The NMDA receptor is involved in a variety of disease states, including:
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:
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