**7. Other factors affecting NMDA receptor function**

**5. NMDA receptor dysregulation and hypofunction in schizophrenia**

phenotypes of the disorder.

6 Schizophrenia Treatment - The New Facets

locomotor activity [27].

disorder [31, 32].

**6. High‐risk genes implicated in schizophrenia**

A major finding discovered by functional imaging studies was reduced activity in the dorsolateral prefrontal cortex (dlPFC) in patients with schizophrenia. The overall reduc‐ tion in neuronal activity in the dlPFC could explain the cognitive deficits and negative symptoms. There is consensus that NMDA receptor hypofunction is strongly associated with the pathophysiology of schizophrenia. In human studies, single‐photon emission computed tomography (SPECT) shows "hypofrontality" patients suffering from schizo‐ phrenia [22]. Furthermore, there are genetic implications that show single‐nucleotide polymorphisms (SNPs) and a reduction in NR1 protein and mRNA in the dorsolateral prefrontal cortex in postmortem subjects of schizophrenia [9, 23]. Additionally, exome sequencing of patients with schizophrenia also displays disruptive mutations in genes that encode NMDAR subunits and NMDA receptor‐associate scaffolding proteins, such as PSD‐95 and SAP102 [24, 25]. These findings would suggest a lack of and/or function at the postsynaptic membrane of excitatory synapses that could be responsible for the cellular

Noncompetitive NMDA receptor antagonists such as PCP, MK‐801, and ketamine have been extensively used to study the symptoms associated with schizophrenia in both human sub‐ jects and animal models [26]. Indeed, these studies have shown to mimic the effects of schizo‐ phrenia, corroborating the glutamatergic hypofunction hypothesis. Individually, PCP induces psychotic symptoms in healthy humans that resemble schizophrenic‐like behavior; MK‐801 elicits positive and negative symptoms; and lastly ketamine administration was shown to imitate the positive, negative, and cognitive deficits seen in schizophrenia [11]. In rats, NMDA receptor antagonists cause deficits in working memory, executive functions, and enhanced

High‐risk genes associated with schizophrenia such as DISC1, dysbindin, neuregulin, COMT, and G72/G30 genes, responsible for neurodevelopment, neuronal growth, and migration, have all shown to be involved in NMDA dysfunction leading to schizophre‐ nia [15]. The most prominent of the genes is *D*isrupted in *schizophrenia* 1 (DISC1), which acts as a scaffolding protein involved in the formation of protein complexes important in neurodevelopment, microtubule network dynamics and axonal elongation [28, 29]. Despite the controversy and debate [16, 30], evidence shows that schizophrenic patients contain DISC1‐SNPs that cause a decrease in DISC1‐interacting protein expression levels, such as NMDA receptors. In DISC1 animal models, mice with point mutations in the gene or truncated forms of DISC1 display molecular, cellular, and behavioral phenotypes that are analogous to schizophrenia. DISC1 is especially susceptible to mutations due to envi‐ ronmental stressors during neurodevelopment that may lead to the pathogenesis of the Environmental factors during development, such as infection, drug use, parental age, prena‐ tal and early postnatal or childhood stress, have all been linked to the emergence of schizo‐ phrenia [33]. In addition, NMDA receptor function is susceptible to the latter environmental risk factors during adolescence, potentially contributing to the onset of the disorder [6, 33, 34]. This could be due to an alteration in NMDA receptor gene expression, as major transcrip‐ tional factors such as the cAMP response element binding protein (CREB) are extremely sen‐ sitive to environmental stimuli [35]. Previous studies describe that neurodevelopment in the prefrontal cortex is altered in patients with schizophrenia due to a substantial increase in synaptic elimination of glutamatergic excitatory synapses [36].

NMDA receptors are also influenced by posttranslational modifications such as ubiquitina‐ tion, palmitoylation, and phosphorylation [34]. NMDA receptor phosphorylation is respon‐ sible for regulating receptor trafficking, stabilization, kinetics of the channel, and kinase activation. These processes are important for synaptic plasticity during neurodevelopment and if dysregulated could be highly responsible for the pathologies of schizophrenia [7]. NMDA receptor subunits are phosphorylated at serine/threonine and tyrosine residues, providing substrate sites for kinases such as Src family of kinases (SFK), casein kinase 2 (CK2), cAMP‐dependent protein kinase A (PKA), cyclin‐dependent kinase 5 (Cdk5), pro‐ tein kinase C (PKC), and Ca2+/calmodulin‐dependent protein kinase II (CaMKII) [37–40].

Other modification processes such as palmitoylation and ubiquitination have also been directly linked to schizophrenia [41]. There is evidence of NMDA receptor dysregulation due to anomalous modifications that could potentially lead to neuropsychiatric disorders. Palmitoylation is a process that allows the covalent attachment of palmitate group to the cys‐ teine residues of proteins that are facilitated via thioester bonds. Recently, it has shown to be involved in regulating NR2 subunit trafficking during neurodevelopment and synaptic plasticity [42] and is altered in a mouse model of 22q11.2 deletion syndrome. Ubiquitination is a process involved in the targeting and removal of proteins and is responsible for regulating NMDA receptors degradation during development. Specifically, subunits such as NR1 and NR2B undergo polyubiquitination at the synapse [41]. Nonetheless, palmitoylation and ubiq‐ uitination require further investigation in its role in NMDA receptor regulation and potential implication in schizophrenia.
