It is with great interest we have read the article “GLYX-13 Ameliorates Schizophrenia-Like
Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1” (Zhou et
al., 2018).
Interestingly, this study showed that GLYX-13 prevents hippocampal N-methyl-D-aspartate
receptor subtype 2B—Disrupted in schizophrenia 1 (GluN2B-DISC1) signaling and behavioral
changes induced by schizophrenia-mimetic drug MK801 in mice. To confirm GluN2B directly
regulating DISC1, these researchers showed that the effects of GLYX-13 were vanished
after GluN2B knockdown in mice.
GLYX-13 is an amidated tetrapeptide. Studies have shown that GLYX-13 can specifically
bind to the glycine site of N-methyl-D-aspartate receptors (NMDARs) and act as a partial
agonist of GluN2B-containing NMDARs (Moskal et al., 2005; Stanton et al., 2009). GLYX-13
improves learning and increases the magnitude of LTP in rat hippocampus (Zhang et
al., 2008). Both GLYX-13 and ketamine have antidepressant-like effects, while GLYX-13
has fewer psychotomimetic side effects than ketamine in both humans and rats (Burgdorf
et al., 2013; Moskal et al., 2014). According to previous study, both GLYX-13 and
ketamine are able to increase cell surface protein expression of GluN2B in rats (Burgdorf
et al., 2013). This might help to explain similar antidepressant effects of these
two compounds. However, the mechanism how GLYX-13 causes less side effects is still
unclear. Interestingly, memantine, another weak NMDAR modulator, also shows fewer
side effects than other NMDAR antagonists in treating Alzheimer's disease (Parsons
et al., 1999). Therefore, it is important for the treatment of psychiatric disorders
to understand how GLYX-13 and other NMDAR modulators affect the neuronal system in
psychiatric disorders without causing serious side effects.
Although GluN2B-containing NMDAR hypofunction and DISC1 alteration are implemented
in the neuropathology of schizophrenia (Callicott et al., 2005; Geddes et al., 2014),
the mechanism of their possible interactions are not clear. In fact, dysfunction of
GluN2B is involved in a number of severe mental disorders (Moghaddam and Javitt, 2012;
Paoletti et al., 2013). GluN2B is found to be over-activated in Alzheimer's disease
(Paoletti et al., 2013). Furthermore, GluN2B antagonists reduce amyloid β-induced
synaptic deficits and impairs long term potentiation. (Rönicke et al., 2011) Conversely,
GluN2B hypo-activity is found in hippocampus accompanied by cognitive impairment and
memory loss in rats (Clayton et al., 2002). In clinical studies, GluN2B antagonists
exacerbate the schizophrenia-like symptoms in both healthy people and patients (Moghaddam
and Javitt, 2012), while antipsychotic drug olanzapine can activate GluN2B via phosphorylation
of the GluN2B at Y1472 (Zhang et al., 2016).
Moreover, GluN2B has a number of phosphorylation sites, which could be responsible
for GluN2B function. For example, phosphorylation of Y1472 attenuated the internalization
of GluN2B (Roche et al., 2001). In this paper (Zhou et al., 2018), GluN2B changes
were found, which could be due to alterations of the internalization. An early study
has shown that Casein Kinase 2 (CK2) might be responsible for this internalization
(Sanz-Clemente et al., 2010), therefore a detection of CK2 might help to clarify the
internalization process of GluN2B.
In addition, due to the slow deactivation kinetics of GluN2B containing NMDARs (Cull-Candy
and Leszkiewicz, 2004), activated synapses with GluN2B type NMDARs exhibit a strong
Ca2+ influx. The Ca2+ influx in turn regulates downstream Ca2+-dependent proteins
such as CaMKII and leads to activity-induced gene expression, synaptic plasticity
and neurite growth (Sanz-Clemente et al., 2013; Barcomb et al., 2016). Thereafter,
GluN2B-containing NMDARs regulate neurite growth and synaptic plasticity (Brigman
et al., 2010).
It is noteworthy that GluN2B interacts with dopamine receptor D2 receptor (D2R) (Fan
et al., 2014). D2R can physically interact with GluN2B in the post synaptic density
(PSD) of the striatum in rats (Liu et al., 2006). Meanwhile, the binding of GluN2B
with D2R can significantly affect the phosphorylation of S1303 of GluN2B, and thus
affect CaMKII activity and synaptic plasticity. The author also found the binding
sequence of D2R is TKRSSRAFRA (amino acid position 225–234) located in the third intracellular
loop of D2R. Co-immunoprecipitation study also confirmed that GluN2B and D2R are tightly
associated. Moreover, the activation of D2R by cocaine can significantly increase
this complex formation and thus reduces NMDAR mediated currents due to dephosphorylated
S1303 of the GluN2B subunit (Liu et al., 2006). Furthermore, another study also demonstrated
D2R over-activation reduces spine density via GluN2B-dependent pathways in mice (Jia
et al., 2013).
The recent manuscript of Zhou et al. showed that GluN2B hypofunction is highly related
to the reduction of DISC1. Interestingly, DISC1 binds to D2R, and the binding site
is located at amino acid positions 211–225 (Su et al., 2014), which is close to the
GluN2B binding site and also located in the third intracellular loop of D2R. Primary
cell culture studies have shown that D2R and DISC1 can form a complex, which is regulated
by the activity of D2R (Su et al., 2014). Studies have shown that increased numbers
of D2R-DISC1 complexes can be identified in post-mortem brains from schizophrenia
patients and that interruption of D2R-DISC1 complex is correlated with antipsychotic
effects in several mouse models (Dahoun et al., 2017). Additionally, phosphorylation
of GSK-3α/β has been confirmed to be affected by D2R-DISC1 complex (Su et al., 2014).
Therefore, GluN2B might interact with DISC1 through D2R and regulate its downstream
GSK-3α/β signaling pathways. Furthermore, it is well known that D2R is one of the
main targets of psychotherapy for schizophrenia and virtually all antipsychotic drugs
have D2R antagonistic properties. Therefore, the involvement of D2R can connect DISC1
and GluN2B and provide a potential target for schizophrenia therapy.
Author contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.