**5. NMDA receptor dysregulation and hypofunction 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 phenotypes of the disorder.

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 locomotor activity [27].
