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Advanced Neurology NMDA receptors in neuropsychiatric diseases

been found to be related to many diseases, including the which attenuated epilepsy [313] . The other mutation
ID, autism spectrum, and epilepsy; the function of some GluN2A_N615K is in the channel pore of M2 TMD
of the mutations has been studied, while others remain domain. The patient was a 3-year-old female with abnormal
unclear. The function of mutations, including D227H, electroencephalogram, developmental delay, and early-
R306E, A349S, S549R, P557R, M641I, and N650K, has not onset epileptic encephalopathy [320] . The GluN2A_N615K
been studied by biological techniques [306,307] . The mutations mutation changed the channel characteristics, including
of D552E, Q556*, S560dup, P557R, G620R, Y647S, G815R, the decreased Ca permeability and Mg sensitivity [321-323] .
2+
2+
F817L, and G827R are loss-of-functions. The S560 is located The reduction of Mg sensitivity to NMDARs increased
2+
in pre-TM1 region, and the mutation of S560dup decreases the NMDAR current.
the activity of NMDARs and changes the structure of the Meanwhile, the mutations of GluN2A are loss-of-function.
pore region [308] . The G815R and F817L mutations are The GluN2A_D731N was found in a child with developmental
adjacent to each other, thus their functions are similar, that delay and epilepsy. The missense mutation is in the ABD of
is, they decreased sensitivity to glutamate and glycine [309] . GluN2A. The results indicated that the mutation decreased
However, the E662K, A645S, and R844C mutations did not the NMDAR current, glutamate sensitivity, and enhanced
change the function of NMDARs [309-312] . On the contrary, the potency of NAM [324] . The GluN2A_V685G is located
the mutations of Y647C, R659W, and R794Q enhanced the in the S2 of ABD region and caused the developmental
function of NMDARs [306] . The R659W and R794Q enhance delay and epilepsy. The mutation caused a low glutamate
the potency of glutamate and glycine, while the mutation potency with NMDAR and decreased NMDAR current
of Y647C increases potency of glycine, but not glutamate. with reduced surface expression [325] .

3.10.2. The GluN2A mutations Besides, the mutations also lead to impairment in
GluN2A subunit is encoded by GRIN2A in the human trafficking. The GluN2A_S1459G, which is located in
chromosome 16p13. More than 240 mutations have been the CTD-related to the protein trafficking of GluN2A,
found in GRIN2A. Many patients had normal delivery at was found in the epilepsy patients [314] . The GluN2A_
birth, with good appearance, facial expression, and vital S1459G induced the impaired binding with SNX27 and
signs scores. However, the patients at the 1 year after PSD95, which led to deficits in NMDAR trafficking and
st
birth may begin to exhibit neurological abnormalities, spine density, and synaptic transmission in excitatory
[326]
such as abnormal electroencephalogram and myoclonic neurons .
convulsions [313] , and then progress to epilepsy, which is From the studies, we understand that the mutations
possibly due to a gradual increase in GluN2A expression may exist in any domains of GluN2A to cause the
during development . Some studies indicated that disorders. Since each mutation is specific, we need to better
[47]
the patients carrying GluN2A mutations were more understand the pathogenesis and changes in function of
likely to show epilepsy, such as benign focal epilepsy the mutation so as to increase the efficacy of targeted
with centrotemporal spikes and Landau-Kleffner therapy in the patients.
syndrome [314-316] . Moreover, the mutations of GluN2A can
produce different effects: gain-of-function and loss-of- 3.10.3. The GluN2B mutations
function. GRIN2B gene encodes the GluN2B subunit and is in the
Some mutations are gain-of-function. The GluN2A_ human chromosome 12p13. Over 200 mutations have
N447K is found in a male patient with Rolandic epilepsy been found in GRIN2B in the patients not only with
[325,327]
and is located in the S1 domain of ABD. The GluN2A_ epilepsy, epileptic encephalopathy , intellectual
[320,325,327,328]
[320,325,327]
N447K enhanced the current density of NMDAR by disability , and ASD , but also with the
[329]
[330-333]
electrophysiological recording. The potency of glutamate AD and schizophrenia . The mutations exist in
was increased, while the inhibition of Mg was decreased all regions of GluN2B. Some of the mutations have been
2+
by GluN2A_N447K. Lamotrigine and valproate treatment functionally analyzed.
could rescue the epilepsy in patient [317] . The patient is a child Many GluN2B mutations are loss-of-function in patient
with impaired cognitive and epileptic encephalopathy. with intellectual disability or ASD. The GluN2B_E413G
Another mutation, GluN2A_L812M, is located in the is located in the ATD domain, which is adjacent to the
linker between S2 of ABD and M4 of TMD. Studies have glutamate-binding site. The E413G reduced the potency
shown that the GluN2A_L812M and M817V enhanced the of glutamate and deactivation, resulting in the loss-of-
open probability and potency with glutamate and glycine of function of NMDAR [334] . Another study reported the
NMDAR, and decreased the inhibition of Mg 2+[318,319] . The function of GluN2B_C456Y mutation. They constructed
patient with GluN2A_L812M was treated by memantine, the heterozygous GluN2B_C456Y mutation mice and

Volume 1 Issue 2 (2022) 13 https://doi.org/10.36922/an.v1i2.148