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Advanced Neurology NMDA receptors in neuropsychiatric diseases

Thus, the NMDARs undergo various regulation of 2.4.1. LTP
protein synthesis, trafficking, and internalization. These To investigate the possible specific role of GluN2 in synaptic
regulations also ensure the dynamic abundance and plasticity, both genetic and pharmacological approaches
composition of NMDARs on the synaptic membrane, have been applied.
thereby allowing physiological functions regulated by
neuronal activity and plasticity. NMDARs containing GluN2B showed a greater
current and carried more Ca 2+[71] . Besides, GluN2B
[48]
2.4. NMDARs in neuroplasticity preferentially interacts with CaMKII [141] , and it is speculated
Synaptic plasticity refers to the long-lasting change in that the GluN2B subtype is more likely to induce LTP than
morphology and function of synapses caused by the the GluN2A subtype. For example, ifenprodil, the GluN2B
neural activity induced by experience [130] . Two classic antagonist, blocks the pairing-induced LTP in hippocampal
[142]
[143]
types of synaptic plasticity, LTP and LTD, have been slices and in the barrel cortex . Moreover, the GluN2B
studied at hippocampal excitatory synapses; both requires antagonist could block the pairing- and theta burst-induced
[144]
the activation of NMDARs [131] . LTP strengthens synapse LTP in the anterior cingulate cortex at 6–8-week-old mice .
function and is induced by high-frequency presynaptic The tetanus induced-LTP in hippocampal CA3 synapses was
[145]
stimulation, while LTD weakens synapse function and abolished in mice with conditional GluN2B knockout .
requires low presynaptic stimulation to induce. NMDAR- Lacking GluN2B in the Cornu ammonis 1 (CA1), the LTP is
[146]
dependent synaptic plasticity is the basis of learning impaired . Another study showed that LTP is deficient by
[147]
and memory in hippocampus. Blocking hippocampal pairing protocol of GluN2B knockout in the forebrain . LTP
is enhanced when GluN2B is overexpressed in hippocampal
NMDARs before training impairs rodent learning neurons of 4–6-month-old mice [148] . Disruption of the
ability [132,133] , but memory is enhanced after hippocampal- interaction between GluN2B and CaMKII by overexpressing
dependent task training [134,135] .
the CTD of GluN2B eliminates the LTP of 3–4-month-old
In hippocampal synapses, AMPARs and NMDARs mice [149] . Genetic deletion of GluN2A has no effect on the
involve the forms of LTP and LTD. AMPARs and NMDARs LTP in P28 mice, indicating that GluN2B is essential for the
are glutamate receptors that are permeable to Na and LTP [150-152] . Other genetic methods that influence the level
+
K , while all NMDARs and part of AMPARs are also of GluN2B also impairs the induction of LTP. For instance,
+
2+
permeable to Ca . When the post-synaptic membrane is knockout of the KIF17, a protein that transports GluN2B to
at resting potential, NMDARs cannot conduct currents the synapses, reduces synaptic GluN2B and abolishes LTP .
[93]
because Mg blocks the channel pore. When AMPAR Besides, Cdk5 knockout mice show increased GluN2B
2+
current causes local membrane depolarization, Mg is and enhanced LTP [153] . Recently, it has been found that
2+
removed from the NMDAR channel, allowing Ca flow enhanced GluN2A surface and synaptic expression causes
2+
into the cell. LTP and LTD require NMDARs-mediated LTP impairment, likely through compensatory GluN2B
[17]
influx of Ca ; LTP requires a large elevation of Ca in decrease . Hence, GluN2B-containing NMDARs play a
2+
2+
spine while that it is much less for LTD. When NMDARs role in the induction of LTP.
mediate a large influx of Ca , protein kinases, especially However, some studies have shown that GluN2A is
2+
CaMKII acting on receptor proteins, accessory receptors, important for LTP [153,154] . In pharmacological experiments,
or transcriptional regulators increase glutamate receptor blocking of GluN2A by NVP-AAM077 could prevent
activity and/or levels in the synapses, thus inducing the tetanus- and pairing-induced LTP in 3–4-week-old rats,
induction and maintenance of LTP [136,137] . When NMDAR- while the ifenprodil and Ro 25-6981, the antagonists
mediated Ca elevation is modest, Ca /calmodulin- of GluN2B, have no effect on LTP but could block the
2+
2+
dependent protein phosphatase, protein phosphatase 1, induction of LTD [154] . Another study that used the same
and calcineurin are phosphorylated and activated, thereby antagonist concentration and rats of the same age found
inducing the dephosphorylation of AMPAR that results that NVP-AAM077 completely blocks LTP, and ifenprodil
in the internalization of AMPAR from the synapses and and Ro 25-6981 partially block LTP [155] . Low Zn which
+
LTD [138-140] . selectively inhibited GluN2A impairs LTP . GluN2A
[72]
[72]
Synaptic plasticity requires Ca , and the composition of knockout mice [156] and deletion CTD of GluN2A mice
2+
NMDARs has different permeability to Ca , which could show impaired LTP in hippocampal synapses.
2+
couple with the phosphatase pathway and downstream For LTP, a possibility is that both GluN2A and GluN2B
signaling to regulate the plasticity [140] . However, how subunits mediate Ca influx, so both subunits are involved
2+
specific subunit composition determines synaptic plasticity in the induction of LTP [157,158] . However, the exact extent of
remains unclear and controversial. involvement of these two subunits in LTP remains unclear.
Volume 1 Issue 2 (2022) 6 https://doi.org/10.36922/an.v1i2.148