# NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality
## 2 Glutamatergic Signaling and Cognitive Deficits in Schizophrenia
### NMDA Receptor-Related Glutamatergic Transmission Impairment in Schizophrenia  
One of the hypotheses of how cognitive deficits develop in schizophrenia is a pharmacological model of NMDAR insufficiency. The model explains the acute and chronic consequences of NMDAR insufficiency for acute symptoms of schizophrenia and hypofrontality. In this model, two clinical situations are reflected: an acute schizophrenic episode and a chronic stage of the disease [18]. The pharmacological model of NMDAR insufficiency shows that both hyper- and hypoglutamatergic states lead to pathologic results in the human brain. An acute receptor antagonist model refers to the short time NMDAR blockade with antagonist phencyclidine (PCP). The blockade of NMDAR on GABA interneurons results in glutamatergic disinhibition in the prefrontal cortex (hyperfrontality) [28]. Neurochemical disturbances, present in the human brain in the acute phase of schizophrenia, resemble the changes observed when NMDAR antagonists are administered directly into different areas of the brain [29]. For example, a significant increase of glutamatergic activity in the cingulate gyrus was observed both in patients with early psychosis [30] and in its prodromal phase [31]. In animal models, a single dose of PCP or ketamine, the dissociative anesthetics, and NMDAR ionic channel blockers, induces neurotoxicity and as a consequence, a degeneration of neurons in many rat brain regions [32]. Finally, an administration of ketamine to healthy volunteers induces an increase of glutamine excretion in the brain [32]. It is worth mentioning that both ketamine and esketamine, as well as newest the NMDAR inhibitors, e.g.,  
Figure 1: The scheme of N-methyl-D-aspartic acid (NMDA) receptor structure with its main binding sites in the context of an agonistic/antagonistic influence of the most important native and exogenous ligands. rapastinel or apimostinel, are recently considered as potentially promising factors in the therapy of treatment-resistant depression and mood disorders [33; 34]. The chronic PCP model explains the link between NMDAR insufficiency and hypofrontality [18]. Long-term administration of PCP inhibits glucose metabolism in rat prefrontal cortex and decreases expression of glutamate decarboxylase--the protein marker of GABA interneuron activity. It is also suggested that a decrease of cortical GAD67 expression in schizophrenia can impair neuroplasticity and can be involved in the hypofrontality arising [35]. NMDARs play a crucial role both in the origin and function of brain GABA-ergic interneurons, especially chandelier and basket cells [36], being responsible for all behavioral effects occurred after application of their modulators [37]. A unique and crucial role is currently ascribed to GABA-ergic parvalbumin neurons [38]. A decreased parvalbumin expression in dorsolateral prefrontal cortex and abnormal gamma band oscillations in schizophrenic patients may be connected with GABA-ergic neurons impairment [39; 40]. Furthermore, the NMDAR hypofunction in the cortical neurons can also trigger overstimulation of GABA-ergic cells in the central tegmental area, disturb the mesocortical dopaminergic pathway activity, and cause negative and cognitive symptoms of schizophrenia [41]. The expression of serotonin receptor 5-HT\({}_{1A}\) in the prefrontal cortex is increased but 5-HT\({}_{2A}\) is reduced, and that may be associated with the pathogenesis of emotional disturbances typical for schizophrenia [42]. In schizophrenia-suffering patients, the same as in people abusing PCP, symptoms of hypofrontality and GABA receptor deficiency are observed. It was shown that the hypofrontality symptoms are maintained even if GABA receptor functioning is restored by clozapine [18]. In the acute phase of schizophrenia, NMDAR insufficiency on GABA-ergic interneurons disinhibits glutamatergic, serotoninergic, and dopaminergic transmission (hyperfrontality).