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Advanced Neurology NMDA receptors in neuropsychiatric diseases

low-dose NMDAR antagonists has shown significant It has been suggested that over-response of fear
efficacy but minimal side effects [282] , although the potential function in the amygdala and a combination of weakened
advantage also requires further validation. inhibitory effects of the projection from prefrontal cortex
to amygdala may lead to PTSD [299] . The functional brain
3.8. Neuropathic pain circuits require the proper synaptic connectivity which
Neuropathic pain is a type of chronic pain induced by can attribute to glutamate with its role in maintenance
the damage of neurons or nerves in the nervous system. the neuronal activity [300] . Ketamine plays a crucial role in
During injury and inflammation, glutamate is released to repairing the synaptic network and also shows positive
activate NMDARs in the peripheral terminals of primary effects on the PTSD [301,302] . The benefits of ketamine in
sensory afferents, leading to pain-related behaviors [283] . PTSD may result from its anti-depressant and anti-
During sensitization of the pain, GluN2B expression is inflammatory effects that improve the brain-derived
increased in the nociceptive neurons in the dorsal horn of neurotrophic factor levels and further re-establish the
the spinal cord, a process that NMDARs activity appears neuronal connectivity [303] . High activity of NMDAR could
to be involved [283,284] . In animal models of peripheral nerve impair formation of spontaneous intrusive memories that
injury, NMDA-activated whole-cell current and calcium may contribute to the development of PTSD [302] . A study
influx in spinal lamina II neurons appear to be increased on rat models of PTSD-induced by contextual fear showed
in nerve-ligated rats [285] . The phosphorylation of GluN1 that the level of brain-derived neurotrophic factor was
subunit in the dorsal horn is increased in partial ligation strongly reduced, which could be reversed by ketamine
of the sciatic nerve [286] . However, the total protein levels of treatment, and NMDAR inhibition interrupted the
GluN1 and GluN2A-D subunits were unchanged in the consolidation of fear conditioning related to hippocampus
spinal cord after nerve injury [286,287] . Therefore, increased and hypothalamus-pituitary-adrenal axis [303-305] . Taken
NMDAR phosphorylation may increase surface NMDAR altogether, the hyperactivity of NMDAR is tightly linked
function and is critical for central sensitization induced by to PTSD and may lead to synaptic abnormalities and
nerve injury. decreased expression of brain-derived neurotrophic factor
Blocking NMDARs could reduce the hypersensitivity especially under traumatic event. Ketamine is currently
of spinal dorsal horn neurons in neuropathic pain an effective pharmaceutical intervention for PTSD. In
models. Memantine, ketamine, and MK-801, which are the future, the studies should focus on optimization of
the NMDAR antagonists, attenuate evoked responses of ketamine with appropriate therapeutic dose and duration,
dorsal horn neuron in spinal nerve-ligated rats [288] . Besides, and on reducing the side effects.
a study showed that ifenprodil, a GluN2B subunit-specific 3.10. NMDARs mutations in diseases
antagonist, reduces the amplitude of NMDAR currents
in nerve-ligated mice [289] . In clinic, intravenous infusion Mutations in NMDARs are related with neuropsychiatric
of ketamine can relieve pain in patients with refractory diseases. Nowadays, the pathogenesis of and therapy
complex regional pain syndrome, but does not prevent development for brain diseases can be explored using
chronic neuropathic pain caused by thoracotomy [290-292] . genomics approaches following the emergence of whole-
Intravenous infusion of amantadine, another NMDAR exome/genome sequencing and targeted therapy. Human
antagonist, reduces persistent neuropathic pain in genetics studies indicated that more than 500 variants of
cancer patients after surgery, but often causes intolerable NMDARs subunit mutations have been found in patients
side effects [293,294] . Therefore, there could be additional with brain disorders, such as intellectual disability,
mechanisms underlying the enhanced NMDAR activity hyperactivity disorder, ASD, schizophrenia, or epilepsy.
after nerve injury. Further studies along this direction These mutations are more prevalent in the GluN2A and
may facilitate the development of neuropathic pain GluN2B subunits of the amino terminal domain (ATD),
therapies. ABD, TMD, and CTD regions. Discovering and analyzing
the function of these mutations can help determine the role
3.9. Post-traumatic stress disorder (PTSD) they play in these neuropsychiatric disorders. In addition,
PTSD is a complex and chronic neuropsychiatric disorder functional analysis of these mutations can advance the
characterized by recurrent appearance of unpleasant or understanding in the etiology of the disease and facilitate
even painful memories resulted from traumatic events, the formulation of treatment plans in clinic.
especially for the military members and also people who 3.10.1. The GluN1 mutations
have recently been infected with COVID-19 [295-297] . The
symptoms severely impair physical and mental health and GluN1 subunit is encode by GRIN1, which is located in
lower the quality of life [298] . human chromosome 9q34. Many mutations in GluN1 have

Volume 1 Issue 2 (2022) 12 https://doi.org/10.36922/an.v1i2.148