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excitatory postsynaptic potentials, which can remove this effect. Several agonists and antagonists have been
the Mg block. Glycine and its analog D-serine can developed for laboratory research or used as tools in
2+
amplify the response of NMDARs to activate them the discovery of new drugs targeting NMDARs such
together with glutamate. [4] as, D-serine, L-alanine as agonists, and amantadine,
ketamine, methoxetamine as antagonists.
Location of NMDA receptor
NMDA receptors are mainly distributed in the CNS, Discovery of anti-NMDA receptor encephalitis
and contribute to excitatory synaptic transmission. Several cases of neural deficiency accompanied with
However, NMDARs are also expressed in the peripheral teratoma were seen from 1997 to 2004. [13] In 2005,
nervous system (PNS), for example, in the peripheral Vitaliani et al. [14] analyzed four patients diagnosed with
terminals of primary afferent nerves innervating the paraneoplastic encephalitis and five patients who were
colon. NMDARs in PNS contribute to nociceptive reported having similar symptoms. They found that all
[5]
stimulus, pain in facial muscles, and edema. Regions the patients were females, and had teratoma. Most of the
of the brain that prominently express NMDARs include patients experienced changes in their personalities, loss
hippocampus, dentate gyri, forebrain cortex, anterior of short-term memory, seizures, central hypoventilation,
cingulate cortex, and piriform cortex. Other areas such and illusions. Abnormal immune systems were found
as corpus striatum, thalamus, and granule cells in in all patients. [14] Two years later, Dalmau et al. [15] found
the cerebellum also express high levels of NMDARs. that serum and cerebrospinal fluid (CSF) samples
Early studies had shown that NMDARs were mainly from these patients showed positive immunochemistry
located in the postsynaptic membrane, especially in reaction with the rat hippocampus. Finally, they found
the postsynaptic density (PSD), for example, in the an antibody that could bind to NMDAR expressed in
dendritic spine in excitatory neurons. However, recent cultured neurons or human embryonic kidney 293
[6]
research has indicated a more diverse distribution (HEK 293) cell membranes in an unregulated manner.
of NMDARs not only in PSD, but also in extra-PSD, The term “anti-NMDAR encephalitis” was coined in
presynaptic, and extra-synaptic regions. Typical that year. In 2008, the antibody was shown to bind to
[7]
examples of extra-synaptic NMDARs are in cerebellum the NR1 subunit of NMDAR, resulting in the loss of its
astrocytes and retina ganglion. Factors that influence ion channel function. [16]
the activation of extra-synaptic NMDARs include the
location and activity of neurons, the transporter in The first case of limbic encephalitis with teratoma
astrocytes, and glutamate spillover in synapses. [8] was reported in 2009. Since the antibody could not be
detected in serum or CSF, it could not be ascertained
Functions of NMDA receptor whether this case was an anti-NMDAR encephalitis. [17]
NMDA receptors are involved in the development of
the nervous system, including the survival of neurons, Probable mechanism of anti-NMDA receptor encephalitis
maturation of dendrites and axons, synaptic plasticity, synaptic plasticity
and formation of neural circuits. In addition, long-term The autoantibody in the patient’s CSF could reduce the
potentiation effect mediated by NMDARs is one of the NMDAR clusters in the synapse by binding, cross-linking
basic mechanisms in learning and memory. It has been and internalization. The reduction was reversible, and
[9]
proven that over-activation of NMDARs is a potential dependent on the titer of the autoantibody. Integrality
mechanism for the occurrence of seizures, dementia of the neurons, synapses, receptors or proteins in the
and stroke, while the under-activation of NMDARs is synapse was not harmed by the antibody. The density
involved in schizophrenia-like symptoms. [10,11] In addition, of the NMDAR clusters could recover four days after
NMDARs are known to mediate central sensitization in the deletion of the autoantibody. [18]
pathogenesis of chronic pain after nociceptive stimulus.
[12]
Therefore, NMDARs play a very important role in CNS. Progress after discovery of anti-NMDA receptor encephalitis
After the discovery of anti-NMDAR encephalitis,
Factors regulating NMDA receptor activity the diagnosis of some clinical signs and syndromes
The activity of NMDARs is regulated by several factors. such as catatonia, subacute confusion of memory,
Glycine can amplify the response of NMDARs to seizures, abnormal movements and limbic encephalitis
glutamine through allosteric effect after binding to NR1 had to be changed. Other forms of encephalitis
subunit. Polyamines can also potentiate the response mediated by autoantibodies against synaptic receptors
of NMDARs to glutamine, while zinc ion can block were found later, such as anti-AMPA receptor,

18 Neuroimmunol Neuroinflammation | Volume 1 | Issue 1 | June 2014