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Advanced Neurology NMDA receptors in neuropsychiatric diseases

found that the protein levels of GluN2B was decreased. function. Inhibition of NMDAR with non-competitive
Besides, the NMDAR current was reduced and the LTD antagonists is the most attractive therapeutic intervention,
was impaired, while the LTP was normal. The behavior data because the effect of antagonists requires pre-activation of
showed that the mice represented the anxious behavior the NMDA receptor [340] . However, NMDAR hypofunction
with normal social interaction. In rescue experiments, the has an influence on the brain function. Even low doses of
D-cycloserine had an effect on the NMDAR currents and NMDAR antagonists can cause decreased excitability of
LTP and recued the impaired behavior in adult mice [335] . NMDAR, leading to memory dysfunction and learning
The mutation GluN2B_C461F is located in the S1 domain disabilities. Besides, enhancing the function of NMDARs
of ABD in patient with Lennox-Gastaut syndrome and may cause NMDAR hyperexcitability due to the inability to
autism. Functional analysis described the C461F mutation distinguish between extrasynaptic and synaptic NMDARs.
decreased the glutamate potency [327] . In the same study, the Comprehensive weighing of the benefits versus adverse
P553L was found in the patient with intellectual disability. effects need be carried out during the clinical development
The mutation, which is located in the pre-MI domain, of drugs targeting NMDARs.
decreased the glutamate potency and NMDAR current 4. Summary
in the neurons [327] . Another study found the mutation,
which, however, mutated to the threonine (P553T), at the NMDAR plays an important role in many processes,
same site. The mutation was found in a 5-year-old patient including learning and memory, development, and
with Rett-like syndrome. The P553T reduced the potency neuroplasticity. Many functions of NMDAR depend
of glutamate, NMDAR currents and spine density in the primarily on the GluN2 subunit. GluN2 subunits are
neurons. Furthermore, the D-serine could restore the mainly expressed in the cortex and hippocampus, and they
deficits induced by GluN2B_P553T [336] . differ in expression patterns, protein trafficking, channel
dynamics, synaptic plasticity, and neuropsychiatric
The mutations of N615I and V618G are gain-of- disorders. This difference also determines the different
function and found in the patients with West syndrome functions of NMDAR. In addition, the composition
and intellectual disability [337] . The two mutations reduced of the NMDAR subunit is also regulated by neural
the inhibition of Mg , although the glutamate potency was activity, which, further, indicates that the composition of
2+
unchanged. Furthermore, the mutation of R540H increased NMDARs is consistent with neural function. However, it
the sensitivity to glutamate and Ca permeability [338] . is still difficult to distinguish the functions and effects of
2+
The gain-of-function mutations may lead to neuronal individual subunits, which also leads to the difficulty in
hyperexcitability, resulting in the disorders. Therefore, we clinical treatment of neuropsychiatric disorders. Therefore,
can treat the diseases by inhibiting NMDAR function in in addition to using new drugs and genetic approaches to
gain-of-function mutations. specifically target different subunits and related signaling
3.11. The challenge and opportunity in treatment of pathways in the treatment of neuropsychiatric disorders,
diseases it would be also interesting to identify the auxiliary
subunits of NMDAR, which is involved in the regulation
In biological experiments, the addition of glycine, of the ions accessibility, and how this interaction affects
D-serine, and D-cycloserine can enhance the function of the downstream signaling pathways may contribute to the
NMDAR, which can provide a new drug choice for clinical understanding of the cellular mechanism in different brain
use as NMDAR potentiators [336] . Besides, in some studies, diseases. The double-sided function of NMDAR poses great
patients carrying GluN2A and GluN2B mutations were challenges for clinical application, so we still need to make
treated with drugs, such as memantine and the blocker of continuous efforts in the treatment of neuropsychiatric
NMDARs [319] . Likewise, the other drugs, such as ketamine, disorders targeting NMDARs.
magnesium, and TCN-201, have effects on the inhibition of
NMDAR current in vitro [318,319,339] . Since different patients Acknowledgments
respond differently to the drug, personalized treatment is We thank Dr. Jiang Chen and other members in Shi
needed for patients with NMDAR mutations. laboratory for constructive discussions.

However, due to the wide distribution and function
of NMDARs, drugs targeting NMDARs may cause Funding
severe adverse effects limiting their clinical potential. This work is supported by grants from the National
The competitive NMDAR antagonists, which prevent Key R&D Program of China (2019YFA0801603),
glutamate-mediated neurotoxicity by inhibiting NMDAR the National Natural Science Foundation of China
function, could cause extensive inhibition of NMDAR (32170951), the Natural Science Foundation of Jiangsu

Volume 1 Issue 2 (2022) 14 https://doi.org/10.36922/an.v1i2.148