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Advanced Neurology NMDA receptors in neuropsychiatric diseases

and GluN2A was increased in the synaptic region [220] . In is disrupted in mice model of HD [237] . The experiments
addition, the expression of MAGUK protein was decreased, also showed that in the HD model, caspase-6 cleavage, a
which is probably due to the impaired interaction between process of the production of toxic mutation Htt fragments,
MAGUK with GluN2B in the PD models [220] . However, increased extransynaptic NMDA receptor-induced
the GluN2B selective antagonists have inconsistent effects currents, and signaling pathways [237] . In addition, the HD
on PD models and human PD patients [221,222] . However, in mice were treated with memantine, which only antagonized
the rat model of PD, specific interference of GluN2A in extrasynaptic NMDAR at low dose and rescued impaired
synaptic localization can reduce motor dysfunction [223] . learning as indicated by a test on rotarod motor [237] .
Another study also presented the similar results that the
Although these studies help us further understand the
pathophysiology of PD, the disease involves many changes activation of synaptic NMDAR rendered Htt mutation-
expressing cortical cells resistant to cell death, while the
in organs and brain regions. Therefore, a complete cure for activation of extrasynaptic NMDAR rendered the cell more
PD remains a major challenge.
vulnerable to cell death [238] . Clinical trials have shown that
3.3. Schizophrenia treating HD mice with low doses rather than high doses
of memantine rescued adverse neuropathological and
Schizophrenia is psychiatric disorder with hallucinations impaired behaviors [238] .
and delusions (positive symptoms), aversion and anhedonia
(negative symptoms), and cognitive dysfunction [224] . Studies Binding of β-amyloid to synaptic NMDAR increases
2+
have shown that excessive release of dopamine in striatum is post-synaptic Ca level, which impairs synaptic
the reason of the positive symptoms [225] , but the mechanism transmission and further affects LTP/LTD. The
of negative symptoms and cognitive dysfunction remains stimulation of extrasynaptic NMDAR could activate
elusive. Changes in glutamate signal may be a pathological calpain which degrade tau protein to a toxic peptide and
basis for the schizophrenia [226] , especially dysregulated also phosphorylate p38-MAPK signaling pathways and
NMDARs may induce the imbalance between excitation leads to cell death. Moreover, tau protein is required to
and inhibition in PV neuron (Figure 1). transport kinase Fyn to the post-synaptic localization,
and to further promote the interaction with PSD95 and
Studies have indicated that reduction in NMDAR phosphorylation of NMDAR, which lead to the impaired
expression causes schizophrenia-like behavior in mice [227] . LTP/LTD in AD. Dysregulated NMDAR could induce ER
Impaired dopamine release is found in mice with GluN1 stress and DNA damage, probably through the overloading
deletion in PV neurons [228] . Recently, other studies in clinic of Ca ions and related signaling pathways. The impaired
2+
proved the NMDAR hypofunction in schizophrenia. The interaction between PSD95 and NMDAR may also affect
noncompetitive NMDAR antagonists, PCP, and ketamine the synaptic transmission and lead to dopaminergic
could induce schizophrenic phenotypes in people [229-231] . neurons death in PD. Hypofunction of NMDAR affects
Furthermore, the MK-801 also induced the PCP-like the spinogenesis and also reduces the release of dopamine,
behavior in many species [232,233] . The autoantibodies against resulting in an unbalance between excitatory and
NMDARs, which are found in patients with the anti- inhibitory transmission and schizophrenia. Increased level
NMDAR encephalitis, cause NMDAR internalization. of extrasynaptic NMDAR attracts more Ca ions, which
2+
These patients show the symptoms similar to induce mitochondrial dysfunction and further lead to
schizophrenia [234] . neuron death. In addition, caspase 6 cleavage of HTT is
These studies suggested that the NMDAR hypofunction essential to increase the extrasynaptic NMDAR current
may cause schizophrenia, providing new ideas for and subsequent excitotoxicity in HD.
developing treatment of schizophrenia in the future. 3.5. Major depressive disorder (MDD)

3.4. Huntington’s disease (HD) MDD is currently one of the most common mental
HD in human results from an inherited huntingtin (HTT) disorders in the world and frequently occurs as a
[239]
gene defect, which induces progressive degeneration of complication in other diseases . The efficacy of drug
neurons in the brain and impairs movement, cognitive treatment for MDD patients usually lasts from weeks to
functions, and emotions. HD is defined by repeated CAG even years. In addition to its severe effect on the social
mutation in HTT gene [235] . Some studies have indicated the communication and cognitive functioning, the comorbid
NMDAR function is increased in HD mouse models [236] , MDD and anxiety symptoms are also a challenge for
[240,241]
and the balance of synaptic and extrasynaptic NMDAR pharmaceutical approaches .
plays an important role in HD (Figure 1). The data found In 1960s, ketamine, a nonselective NMDAR antagonist,
that the balance of synaptic and extrasynaptic NMDAR was originally developed as an anesthetic [242] . In 2000,

Volume 1 Issue 2 (2022) 10 https://doi.org/10.36922/an.v1i2.148