# NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality
## 2 Glutamatergic Signaling and Cognitive Deficits in Schizophrenia
### NMDA Receptor-Related Glutamatergic Transmission Impairment in Schizophrenia
As a consequence, a down-regulation of receptors occurs and leads to a decrease of dopamine and glutamine turn-over in the prefrontal lobe and to deficit symptoms (hypofrontality), corresponding with a chronic phase of psychosis [7; 43]. Presumably, the repetitive or long-term hyperglutamatergic states induce receptors' adaptation and result in a decrease of neurotransmission in the prefrontal cortex [7]. It should be underlined that some primary functional dysregulations of NMDA receptors may cause monoamine signaling disturbances [44]. Patients suffering from schizophrenia also show significant NMDAR related deficits of neuroplasticity in the auditory cortex with a decrease of cognition. The deficits can be partially reduced with NMDAR agonist D-serine [45]. A piece of interesting information about hypofrontality may be derived from studies on rats prenatally exposed to methylazoxymethanol (MAM). This is a genotoxic agent, that methylates DNA helix and impairs neuronal differentiation and migration. In these animals, some structural mPFC dysfunctions, as well as several schizophrenia-like behavioral abnormalities, were observed [46; 47]. A recent magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) finding on MAM rats proved that hypofrontality observed in young individuals is maintained in adult ones being associated with hyperflexible phenotype and posterior hyperactivity [48]. These novel kinds of basic, noninvasive imaging studies can be clinically translatable and contribute significantly to the development of the early diagnosis of schizophrenia. Several studies confirm the reliability of the long-term PCP administration model. Long-term exposition of rats to NMDAR antagonist decreases brain activity [48] and decreases the dopamine release in the prefrontal cortex and limbic system [49]. Similarly, in humans without schizophrenia, the long-term exposition to PCP decreases the glucose metabolism in the prefrontal cortex [29]. Long-term PCP administration is a cause of apoptosis in the brain cortex. It was confirmed that the apoptosis is related more to the blockade of NMDARs, containing more NR2A than NR2B subunits [50]. In schizophrenia patients, post mortem studies showed changes in the composition of NMDAR subunits in different human brain areas. Despite the fact that the results are frequently inconsistent, they indicate a decrease of NMDAR activity in schizophrenia [27]. Based on the studies, some changes of NMDAR subunit expression in schizophrenia can be characterized. Namely, in people with schizophrenia in the dorsolateral prefrontal cortex, expression of NR1 and NR2A subunits (bothmRNA and protein) is decreased [51; 52; 53]. On the other hand, no changes in cortex expression of NR2 (A, B, and D) and NR3 are observed, except a decrease of NR2C subunit expression in the prefrontal lobe [54; 51]. The transport of the NR2B subunit in the cortex can be disturbed too, so in that way, the activity of NMDARs can be decreased [55]. In the frontal and occipital cortex, NR2A subunit expression is increased [19], while in the parietal cortex the quantity of NR2B subunits increases [56]. In the hippocampus, NR1 expression decreases, but probably more NR2B subunits are synthesized [57]. In the thalamus NR1 subunits are less expressed [19] and in the dorsomedial nucleus the number of NR2B subunits increases [58]. In the putamen the number of NR1 subunits decreases [59]. Because the NR1 subunit is present in each NMDAR, so the decrease of it indicates the decrease of the receptor expression in the striatum. Similarly, in the substantia nigra the number of NR1 subunits is decreased [19]. Still, parts of some studies do not show any abnormalities, e.g., [56]. Some patients suffering from the initial phase of NMDAR autoimmune encephalitis with NR1 antibodies may exhibit schizophrenia-like psychotic behavior [60; 61] or symptoms of hypofrontality [62], however, the vast majority of recent studies do not confirm the presence of IgG-NR1 antibodies in schizophrenia [63; 64].